2-Naphthylimino-1,3-thiazine derivative

ABSTRACT

The formula (I):  
                 
 
wherein each of R 2  and R 3  is, same or different, C2-C4 alkyl or the like; or R 2  and R 3  are taken together with the adjacent carbon atom to form a 5 to 8 membered non-aromatic carbocyclic ring; R 4  is C1-C6 alkyl or the like; X is an oxgen atom or a sulfur atom; A is the group of the formula:  
                 
 
wherein R 1  is, same or different, alkyl or the like; W is C2-C6 alkylene which may contain an optionally substituted heteroatom(s) or the like; n is an integer of 0 to 7, a pharmaceutically acceptable salt, or a solvate thereof.

TECHNICAL FIELD

The present invention relates to 2-naphthylimino-1,3-thiazinederivatives having a cannabinoid receptor agonistic activity andpharmaceutical use of themselves.

BACKGROUND ART

Cannabinoid was discovered as the main active substance contained inmarijuana in 1960 and found to exhibit an activity to the centralnervous system (illusion, euphoria, sensory confusion of time and space)and an activity to the peripheral cell system (immunosuppressiveactivity, anti-inflammatory activity, analgesic activity).

After that, anandamide and 2-arachidonoylglycerol produced fromphospholipid containing arachidonic acid were discovered as anendogenous cannabinoid receptor agonist. These endogenous agonists wereknown to exhibit an activity to the central nervous system and anactivity to the peripheral cell system. It was disclosed in Non-Patent 1that anandamide exhibits an activity to the cardiovascular system.

A cannabinoid type 1 receptor discovered in 1990 was found to distributein the central nervous system such as the brain. Agonists to thisreceptor were found to suppress the release of neurotransmitters tocause central actions such as illusion or the like. A cannabinoid type 2receptor discovered in 1993 was found to distribute in immune tissuessuch as the spleen or the like. Agonists to this receptor were found tosuppress an activation of cells in immunocyte or phlogocyte to exhibitan immunosuppressive activity, an anti-inflammatory activity and ananalgesic activity (Non-Patenrt 2).

It was disclosed in Non-Patent 3 that Δ⁹-tetrahydrocannabinol and thelike exhibit bronchodilatation. Furthermore, It was disclosed in Patent1 that a cannabinoid receptor agonism exhibits an anti-pruritusactivity.

Known as compounds having a cannabinoid receptor agonistic activity areisoindolynone derivatives (Patent 2), pyrazole derivatives (Patent 3),quinolone derivatives (Patent 4 and Patent 5), pyridone derivatives(Patent 6), thiazine derivatives (Patent 7 and Patent 8), and the like.

-   -   Patent 1: WO03/035109    -   Patent 2: WO97/29079    -   Patent 3: WO98/41519    -   Patent 4: WO099/02499    -   Patent 5: WO00/40562    -   Patent 6: WO02/053543    -   Patent 7: WO01/19807    -   Patent 8: WO02/072562    -   Non-Patent 1: Hypertension (1997) 29, 1204-1210    -   Non-Patent 2: Nature, 1993, 365, 61-65    -   Non-Patent 3: Journal of Cannabis Therapeutics 2002, 2(1), 59071

DISCLOSURE OF INVENTION

The present invention provides a cannabinoid receptor agonistic activityand a pharmaceutical composition, an analgesics, a treating agent foralgesic, an antipruritics or a bronchodilator containig themselves as anactive ingredient.

The inventors of the present invention have found that the following2-naphthylimino-1,3-thiazine derivatives have a strong cannabinoidreceptor agonistic activity and a pharmaceutical composition contaningthemselves as an active ingredient is useful for an analgesics, atreating agent for algesic, an antipruritics or a bronchodilator.

The present invention relates to 1) a compound represented by theformula (I):

wherein each of R² and R³ is, the same or different, and each is C2-C4alkyl, C2-C4 alkenyl, C1-C4 alkoxyC1-C4 alkyl, optionally substitutedaminoC1-C4 alkyl, or C3-C6 cycloalkylC1-C4 alkyl; or

R² and R³ are taken together with the adjacent carbon atom to form anoptionally substituted 5 to 8 membered non-aromatic carbocyclic ring oran optionally substituted 5 to 8 membered non-aromatic heterocyclicring;

R⁴ is C1-C6 alkyl, hydroxyC1-C6alkyl, optionally substitutedaminoC1-C6alkyl, or C1-C6 alkoxyC1-C6 alkyl;

X is an oxgen atom or a sulfur atom;

A is the group of the formula:

wherein R¹ is, same or different, alkyl, alkoxy, alkylthio, optionallysubstituted amino, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted aralkyloxy, cycloalkyl, a halogen atom,hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl,carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxylalkyl,alkylthioalkyl optionally substituted aminoalkyl, alkoxyiminoalkyl,alkoxyalkoxy, alkylthioalkoxy, alkoxycarbonylalkoxy, carboxyalkoxy,alkylsulfonyloxy, optionally substituted heteroaryl, an optionallysubstituted non-aromatic heterocyclic group, cyano, cyanoalkoxy, or agroup of the formula: —C(═O)—R^(H) wherein RH is a hydrogen atom, alkyl,optionally substituted aryl, or an optionally substituted non-aromaticheterocyclic group;

W is C2-C6 alkylene which may contain optionally substituted aheteroatom(s) or C2-C4 alkenylene which may contain optionallysubstituted a heteroatom(s);

n is an integer of 0 to 7;

-   a pharmaceutically acceptable salt, or a solvate thereof,-   2) the compound according to 1) wherein R² and R³ are taken together    with the adjacent carbon atom to form an optionally substituted 5 to    6 membered carbocyclic ring, a pharmaceutically acceptable salt, or    a solvate thereof,-   3) the compound according to 1) or 2) wherein W is —CH₂CH₂CH₂—,    —CH₂CH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —N(CH₃)CH₂CH₂CH₂—, or    —CH═CH—CH═CH—, a pharmaceutically acceptable salt, or a solvate    thereof,-   4) a compound of the formula (II):    wherein R¹ is, same or different, alkyl, alkoxy, optionally    substituted amino, a halogen atom, hydroxy, haloalkyl, haloalkoxy,    cyano, or alkoxycarbonylalkoxy;

each of R² and R³ is, same or different, C2-C4 alkyl; or

R² and R³ are taken together with the adjacent carbon atom to form 5 to6 membered cycloalkane;

R⁴is C1-C6 alkyl;

X is an oxgen atom or a sulfur atom;

n is an integer of O to 7;

-   a pharmaceutically acceptable salt, or a solvate thereof,-   5) the compound according to 4) wherein R¹ is a fluorine atom, a    chlorine atom, dimethylamino, cyano, or t-butoxycarbonylmethoxy, a    pharmaceutically acceptable salt, or a solvate thereof,-   6) the compound according to 4) or 5) wherein n is 0 or 1, a    pharmaceutically acceptable salt, or a solvate thereof,-   7) a compound of the formula (III):    wherein R¹ is, same or different, alkyl, alkoxy, optionally    substituted amino, a halogen atom, hydroxy, haloalkyl, haloalkoxy,    cyano, or alkoxycarbonylalkoxy;

each of R² and R³ is, same or different, C2-C4 alkyl; or

R² and R³ are taken together with the adjacent carbon atom to form 5 to6 membered cycloalkane;

R⁴is C1-C6 alkyl;

X is an oxgen atom or a sulfur atom;

Z is —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, or —OCH₂CH₂O—;

n is an integer of 0 to 3;

-   a pharmaceutically acceptable salt, or a solvate thereof,-   8) the compound according to 7) wherein Z is —CH₂CH₂CH₂— or    —CH₂CH₂CH₂CH₂—, a pharmaceutically acceptable salt, or a solvate    thereof,-   9) the compound according to 7) wherein Z is —OCH₂CH₂O—, a    pharmaceutically acceptable salt, or a solvate thereof,-   10) the compound according to any one of 7) to 9) wherein n is 0, a    pharmaceutically acceptable salt, or a solvate thereof,-   11) the compound according to any one of 4) to 10) wherein R² and R³    are taken together with the adjacent carbon atom to form 6 membered    cycloalkane, a pharmaceutically acceptable salt, or a solvate    thereof,-   12) the compound according to any one of 1) to 11) wherein each of    R² and R³ is, same or different, C2-C3 alkyl, a pharmaceutically    acceptable salt, or a solvate thereof,-   13) the compound according to any one of 1) to 11) wherein R⁴ is    methyl or ethyl, a pharmaceutically acceptable salt, or a solvate    thereof,-   14) a pharmaceutical composition which contains the compound    according to any one of 1) to 13), a pharmaceutically acceptable    salt, or a solvate thereof as an active ingredient,-   15) a pharmaceutical composition which contains the compound    according to any one of 1) to 13), which has a cannabinoid receptor    agonistic activity, a pharmaceutically acceptable salt, or a solvate    thereof as an active ingredient,-   16) the pharmaceutical composition according to any one of 14)    or 15) which is useful for an analgesics,-   17) the pharmaceutical composition according to any one of 14)    or 15) which is useful as a treating agent for algesic,-   18) the pharmaceutical composition according to any one of 14)    or 15) which is useful for an antipruritics,-   19) the pharmaceutical composition according to any one of 14)    or 15) which is useful for a bronchodilator,-   20) a method for treating a disease related to a cannabinoid    receptor which comprises administering the compound according to any    one of 1) to 13), a pharmaceutically acceptable salt, or a solvate    thereof,-   21) use of the compound according to any one of 1) to 13) for    manufacturing a treating agent for a disease related to a    cannabinoid receptor, a pharmaceutically acceptable salt, or a    solvate thereof.

The meaning of each term are shown as follows. Each term is used toexpress the same meaning employed alone or in combination with otherterms in the specification.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom, and an iodine atom.

The term “heteroatom” includes a nitrogen atom, an oxygen atom, and asulfur atom.

The term “alkyl” includes straight- or branched chain C1-C10 alkyl.Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, and the like. Especially, preferable isstraight- or branched chain C1-C4 alkyl. For example, preferable aremethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, andt-buty. When number of carbon atom is designated, means “alkyl” havingdesignated number of carbon atom.

The term “cycloalkylalkyl” includes the above-mentioned “alkyl”substituted with one or more the below-mentioned “cycloalkyl”. Examplesare cyclopropylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl,2-cyclohexylpropyl, and the like.

The term “hydroxyalkyl” includes the above-mentioned, “alkyl”substituted with one or more hydroxy. Examples are 2-hydroxyethyl,3-hydroxypropyl, and the like.

The term “alkoxyalkyl” includes the above-mentioned “alkyl” substitutedwith one or more the below-mentioned “alkoxy”. Examples aremethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, and thelike.

The term “alkylthioalkyl” includes the above-mentioned “alkyl”substituted with one or more the below-mentioned “alkylthio”. Examplesare methylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,3-methylthiopropyl, and the like.

The term “optionally substituted aminoalkyl” includes theabove-mentioned “alkyl” substituted with one or more the below-mentioned“optionally substituted amino”. Examples are methylamiomethyl,2-dimethylamioethyl, 2-diethylamioethyl, 3-dimethylamiopropyl, and thelike.

The term “alkoxyiminoalkyl” includes the above-mentioned “alkyl”substituted with one or more the below-mentioned imino group substitutedwith the below-mentioned “alkoxy”. Examples are methoxyimiomethyl,2-methoxyimioethyl, 2-ethoxyimioethyl, 2-methoxyimiopropyl, and thelike.

The term “alkenyl” includes straight- or branched chain C2-C8 alkenylwhich is the above-mentioned “alkyl” having one or more double bond(s).Examples are vinyl, 1-propenyl, allyl, isopropenyl, 1-buteneyl,2-buteneyl, 3-buteneyl, 3-pentenyl, 1,3-butadienyl, 3-methyl-2-butenyl,and the like. Especially, preferable is straight- or branched chainC2-C4 alkenyl. For example, preferable are allyl, isopropenyl, and3-buteneyl. When number of carbon atom is designated, means “alkenyl”having designated number of carbon atom.

The term “alkynyl” includes straight- or branched chain C2-C8 alkynylwhich is the above-mentioned “alkyl” having one or more triple bond(s).Examples are ethynyl, propargyl, and the like. Especially, preferable isstraight- or branched chain C2-C4 alkynyl. For example, preferable ispropargyl.

The term “haloalkyl” means the above-mentioned “alkyl” having one ormore halogen atom(s). Examples are chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, chloroethyl (e.g. 2-chloroethyl),dichloroethyl (e.g., 1,2-dichloroethyl, 2,2-chloroethyl), chloropropyl(e.g., 2- chloropropyl, 3-chloropropyl), and the like. Preferable ishaloC1-C3 alkyl.

The term “C2-C6 alkylene which may contain an optionally substitutedheteroatom(s)” includes straight- or branched chain C2-C6 alkylene whichmay contain one to three heteroatom(s) optionally substituted withalkyl. The above-mentioned “alkyl”, the below-mentioned “aralkyl”, thebelow-mentioned “aryl”, the below-mentioned “heteroaryl”, thebelow-mentioned “acyl”, and the below-mentioned “alkoxycarbonyl” areexemplified as the substituent of a heteroatom(s). Examples are—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂O—, —OCH₂CH₂—, —CH₂CH₂S—, —SCH₂CH₂—, —CH₂CH₂OCH₂—, —OCH₂CH₂O—,—OCH₂O—, —N(CH₃)CH₂CH₂CH₂—, and the like. Preferable are —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH₂O—, and —N(CH₃)CH₂CH₂CH₂—.

The term “C2-C4 alkenylene which may contain an optionally substitutedheteroatom(s)” includes straight- or branched chain C2-C4 alkenylenewhich may contain one to two heteroatom(s) optionally substituted withalkyl. The above-mentioned “alkyl”, the below-mentioned “aralkyl”, thebelow-mentioned “aryl”, the below-mentioned “heteroaryl”, thebelow-mentioned “acyl”, or the below-mentioned “alkoxycarbonyl” areexemplified as the substituent of a heteroatom(s). Examples are—CH═CH—CH═CH—, —CH═CH—O—, —O—CH═CH—, —CH═CH—S—, —S—CH═CH—, —CH═CH—NH—,—NH—CH═CH—, —CH═CH—CH═N—, —N═CH—CH═CH—, and the like. Preferable are—CH═CH—CH═CH—, —CH═CH—CH═N—, and —N═CH—CH═CH—.

The term “cycloalkane” includes C3-C10 cycloalkane. Examples arecyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, and the like. Preferable is C5-C8 cycloalkane. Examples arecyclopentane, cyclohexane, cycloheptane, and cyclooctane. When number ofcarbon atom is designated, means “cycloalkane” having designated numberof carbon atom.

The term “a carbocyclic ring” includes a 3 to 10 membered carbocyclicring which may have one or more a double bond(s) and/or a triplebond(s). Example are cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene,cyclooctene, or the like. Preferable is C5-C8 cycloalkane, and examplesare cyclopentane, cyclohexane, cycloheptane; cycloheptane. When numberof carbon atom is designated, means “a carbocyclic ring” havingdesignated number of carbon atom.

The term “a non-aromatic carbocyclic ring” includes a 3 to 10 memberednon-aromatic carbocyclic ring which may have one or more a doublebond(s) and/or a triple bond(s). Example are cyclopropane, cyclobutane,cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane,cycloheptene, cyclooctene, or the like. Preferable is C5-C8 cycloalkane,and examples are exemplified cyclopentane, cyclohexane, cycloheptane,and cycloheptane. When number of carbon atom is designated, means “anon-aromatic carbocyclic ring” having designated number of carbon atom.

The term “cycloalkyl” includes C3-C10 cycloalkyl. Examples arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, or the like. Preferable is C3-C6 cycloalkyl, and examplesare cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When number ofcarbon atom is designated, means “cycloalkyl” having designated numberof carbon atom.

The term “aryl” includes a C6-C14 aryl, and examples are phenyl,naphthyl, anthryl, phenanthryl, or the like. Especially, preferable arephenyl and naphthyl.

The term “aralkyl” includes the above-mentioned “alkyl” substituted withthe above-mentioned “aryl”. Examples are benzyl, phenylethyl (e.g.,1-phenylethyl, 2-phenylethyl), phenylpropyl (e.g., 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl,2-naphthylmethyl), or the like. Especially, preferable are benzyl andnaphthylmethyl.

The term “heteroaryl” includes C1-C9 heteroaryl having one to fournitrogen atom(s), oxygen atom(s) and/or sulfur atom(s). Examples arefuryl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl,2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl,5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl), thiazolyl(e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g.,3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g.,1,3,4-oxadiazol-2-yl), benzofuryl (e.g., 2-benzo[b]furyl,3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo [b]furyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo [b]thienyl, 5-benzo [b]thienyl, 6-benzo[b]thienyl,7-benzo [b]thienyl), benzimidazolyl (e.g., 1-benzimidazolyl,2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), dibenzofuryl,benzoxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl,6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl,5-cinnolinyl, 6- cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl(e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl,7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl),isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), puryl,pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl,7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g.,1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl),indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), isoindolyl, phenazinyl (e.g., 1-phenazinyl,2-phenazinyl) or phenothiadinyl (e.g., 1-phenothiadinyl,2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl), and the like.

The term “a non-aromatic heterocyclic group” includes a C1-C9non-aromatic heterocyclic group having one to four nitrogen atom(s),oxygen atom(s) and/or sulfur atom(s). Examples are 1-pyrrolinyl,2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino,2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino,tetrahydropyranyl, or the like. Especially, preferable are morpholino,pyrrolidino, piperidino, and piperazino.

The term “non-aromatic heterocyclic ring” includes a C1-C9 non-aromaticring having one to four nitrogen atom(s), oxygen atom(s) and/or sulfuratom(s). Examples are tetrahydrofuran, tetrahydrothiophen, pyrrolidine,tetrahydropyran, piperidine, morpholine, and the like. Especially,preferable are tetrahydrothiophen and piperidine.

The alkyl part of “alkoxy” is defined as the above “alkyl”. Methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the likeare exemplified as “alkoxy”. Preferable is C1-C4 alkoxy, and examplesare methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy,sec-butoxy or t-butoxy. When number of carbon atom is designated, means“alkoxy” having designated number of carbon atom.

The term “haloalkoxy” means the above “alkoxy” substituted with one ormore halogen. Examples are dichloromethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy (2,2,2-trifluoroethoxy), and the like.Especially, preferable are difluoromethoxy, and trifluoromethoxy.

The term “aryloxy” includes an oxygen atom substituted with the above“aryl”. Examples are phenoxy, naphthoxy (e.g., 1-naphthoxy,2-naphthoxy), anthryloxy (e.g., 1-anthryloxy, 2-anthryloxy), phenanthryl(e.g., 1-phenanthryl, 2-phenanthryl), and the like. Especially,preferable are phenoxy and naphthoxy.

The term “aralkyloxy” includes an oxygen atom substituted with the above“aralkyl”. Examples are benzyloxy, phenethyloxy, and the like.Especially, preferable is benzyloxy.

The term “alkoxyalkoxy” includes the above-mentioned “alkoxy”substituted with the above-mentioned “alkoxy”. Examples aremethoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy,1-methoxyethoxy, 2-methoxyethoxy, and the like. Especially, preferableare 1-methoxyethoxy and 2-methoxyethoxy.

The term “alkylthioalkoxy” includes the above-mentioned “alkoxy”substituted with the below-mentioned “alkylthio”. Examples aremethylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy,isopropylthiomethoxy, 1-methylthioethoxy, 2-methylthioethoxy, and thelike. Especially, preferable are 1-methylthioethoxy and2-methylthioethoxy.

The term “carboxyalkoxy” includes the above-mentioned “alkoxy”substituted with one or more “carboxy”. Examples are carboxymethoxy,2-carboxyethoxy, and the like.

The term “alkoxycarbonylalkoxy” means the above-mentioned “alkoxy”substituted with the below-mentioned “alkoxycarbonyl”. Examples aremethoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propoxycarbonylmethoxy,i-propoxycarbonylmethoxy, n-butoxycarbonylmethoxy,i-butoxycarbonylmethoxy, sec-butoxycarbonylmethoxy,tert-butoxycarbonylmethoxy, 2-(tert-butoxycarbonyl)ethoxy,2-(n-pentyloxycarbonyl)ethoxy, 2-(n-hexyloxycarbonyl)ethoxy,n-heptyloxycarbonylmethoxy, n-octyloxycarbonylmethoxy, and the like.Especially, preferable are tert-butoxycarbonylmethoxy and2-(tert-butoxycarbonyl)ethoxy.

The term “cyanoalkoxy” includes the above-mentioned “alkoxy” substitutedwith one or more “cyano”. Examples are cyanomethoxy, 2-cyanoethoxy, andthe like.

The alkyl part of “alkylthio” is defined as above-mentioned “alkyl”.Examples are methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio,n-hexylthio and the like. Especially, preferable is C1-C4 straight- orbranched chain alkylthio, and examples are methylthio, ethylthio,n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, andt-butylthio.

Non-substituted amino, C1-C4 alkylamino, (C1-C4 alkyl)carbonylamino,aryl carbonylamino, N-(C1-C4 alkyl)carbonyl-C1-C4 alkylamino,aralkylamino, C1-C4 alkylsulfonylamino, C2-C4 alkenyloxycarbonylamino,(C1-C4 alkoxy)carbonylamino, C2-C4 alkenylamino, arylcarbonylamino, andheteroarylcarbonylamino are exemplified as “optionally substitutedamino”. Especially, preferable are non-substituted amino, C1-C4alkylamino, (C1-C4 alkyl)carbonylamino, and (C1-C4 alkoxy)carbonylamino.

Methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino,diethylamino, ethylmethylamino, and propylmethylamino are exemplified asC1-C4 alkylamino. Acetylamino, formylamino, and propionylamino areexemplified as (C1-C4 alkyl)carbonylamino. Benzoylamino is exemplifiedas arylcarbonylamino. N-acetylmethylamino is exemplified as N-(C1-C4alkyl)carbonyl-C1-C4 alkylamino. Benzylamino, 1-phenylethylamino,2-phenylethylamino, 1-phenylpropylamino, 2-phenylpropylamino,3-phenylpropylamino, 1-naphthylmethylamino, 2-naphthylmethylamino, anddibenzylamino are exemplified as aralkylamino. Methanesulfonylamino andethanesulfonylamino are exemplified as C1-C4 alkylsulfonylamino.Vinyloxycarbonylamino and allyloxycarbonylamino are exemplified asalkenyloxycarbonylamino. Methoxycaronylamino, ethoxycaronylamino, andt-butoxycaronylamino are exemplified as (C1-C4 alkoxy)carbonylamino.Vinylamino or allylamino are exemplified as C2-C4 alkenylamono.Benzoylamino is exemplified as arylcarbonylamino. Pyridinecarboylaminois exemplified as heteroarylcarbonylamino.

The term “acyl” means carbonyl substituted with the group except for ahydrogen atom. Examples are alkylcarbonyl (e.g., acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloryl, hexanoyl, octanoyl,lauroyl), alkenylcarbonyl (e.g., acryloyl, methacryloyl),cycloalkylcarbonyl (e.g., cyclopropanecarbonyl, cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl), arylcarbonyl (e.g., benzoyl,naphthoyl), and heteroarylcarbonyl (e.g., pyridinecarbonyl). Thesegroups may be substuituted with alkyl, a halogen atom, and the like.Toluoyl which is an example of arylcarbonyl substituted with alkyl andtrifluoroacetyl which is an example of alkylcarbonyl substituted with ahalogen atom(s) are exemplified.

The term “alkoxycarbonyl” means carbonyl substituted with theabove-mentioned “alkoxy”. Examples are methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl,n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, and thelike. Preferable are methoxycarbonyl, ethoxycarbonyl and the like.

Alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), acyl (e.g., formyl,acetyl, propionyl, benzoyl) and the like are exemplified as thesubstituents of “optionally substituted carbamoyl”. The nitrogen atom ofa carbamoyl group may be mono- or di-substituted with thesesubstituents. Preferable are carbmoyl, N-methyl carbmoyl, N-ethylcarbmoyl, and the like as “optionally substituted carbamoyl”.

The alkyl part of “alkylsulfinyl” is defined as the above-mentioned“alkyl”. Methanesulfinyl, ethanesulfinyl and the like are exemplified as“alkylsulfinyl”.

The alkyl part of “alkylsulfonyl” is defined as the above-mentioned“alkyl”. Methanesulfonyl, ethanesulfonyl and the like are exemplified as“alkylsulfonyl”.

The alkylsulfonyl part of “alkylsulfonyloxy” is defined as theabove-mentioned “alkylsulfonyl”. Methanesulfonyloxy, ethanesulfonyloxy,and the like are exemplified as “alkylsulfonyloxy”.

When “optionally substituted aryl”, “optionally substituted heteroaryl”,“an optionally substituted non-aromatic carbocyclic ring”, “anoptionally substituted non-aromatic heterocyclic ring”, “an optionallysubstituted non-aromatic heterocyclic group ”, “optionally substitutedaryloxy”, or “optionally substituted aralkyloxy” has substituebt(s),these groups are substituted at any position(s) with one to four ofsubstituents which may be same or differnt.

Hydroxy, carboxy, a halogen atom (a fluorine atom, a chlorine atom, abromine atom, an iodine atom), haloalkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃),haloalkoxy, alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), alkenyl(e.g., vinyl), formyl, acyl (e.g., acetyl, propionyl, butyryl, pivoloyl,benzoyl, pyridinecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl),alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl), alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl), nitro, nitroso, oxo, optionally substituted amino(e.g., amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino),formylamino, acylamino (e.g., acetylamino, benzoylamino), aralkylamino(e.g., benzylamino, tritylamino)), azido, aryl (e.g., phenyl), aryloxy(e.g., phenoxy), cyano, isocyano, isocyanato, thiocyanato,isothiocyanato, mercapto, alkylthio (e.g., methylthio, ethylthio),alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl), arylsuslfonyl(e.g., benzensulfonyl), optionally substituted carbamoyl, sulfamoyl,formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy,thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureido, amidino,guanidino, formyloxy, thioxo, alkoxyalkoxy, alkylthioalkoxy, and thelike are exemplified as their substituents.

The following groups are exemplified as “R² and R³ are taken togetherwith the adjacent carbon atom to form an optionally substituted 5 to 8membered non-aromatic carbocyclic ring”.

Especially, preferable is 5 or 6 membered cycloalkane formed by R² andR³ taken together with the adjacent carbon atom.

Substsituents groups (Ia) to (Ip) are shown as preferablesubstitsuent(s) groups for (R¹)_(n), R² to R⁴, X, and W of the compoundrepresented by the formula (I).

(R¹)_(n): (Ia) a hydrogen atom, a halogen atom, alkyl, haloalkyl,hydroxy, alkoxy, haloalkoxy, optionally substituted amino, cyano, oralkoxycarbonyl, (Ib) a hydrogen atom, a halogen atom, alkyl, alkoxy,optionally substituted amino, cyano, or alkoxycarbonyl, (Ic) a hydrogenatom, a halogen atom, optionally substituted amino, cyano, oralkoxycarbonyl.

R²: (Id) C2-C4 alkyl or C2-C4 alkenyl, (Ie) C2-C4 alkyl.

R³: (If) C2-C4 alkyl or C2-C4 alkenyl, (Ig) C2-C4 alkyl.

R⁴: (Ih) C1-C8 alkyl or C1-C6 alkoxy, (Ie) C1-C8 alkyl.

X: (Ii) an oxgen atom or a sulfur atom.

W: (Ik) C2-C6 alkylene may contain an optionally substitutedheteroatom(s) or C2-C4 alkenylene may contain an optionally substitutedheteroatom(s), (II) C3-C6 alkylene or C3-C4 alkenylene may contain aheteroatom(s), (Im) C3-C6 alkylene, (In) C3-C4 alkenylene may contain aheteroatom(s)

R² and R³ are taken together with the adjacent carbon atom to form (Io)a 5 to 8 membered carbocyclic ring, (Ip) 5 to 6 membered cyaloalkane.

Examples of preferable group ot the compound represented by the formula(I) contains [(R¹)_(n), R², R³, R⁴, X, W]=[Ia, Id, If, Ih, Ij, Ik], [Ia,Id, If, Ih, Ij, Il], [Ia, Id, If, Ih, Ij, Im], [Ia, Id, If, Ih, Ij, In],[Ia, Id, If, Ii, Ij, Ik], [Ia, Id, If, Ii, Ij, Il], [Ia, Id, If, Ii, Ij,Im], [Ia, Id, If, Ii, Ij, In], [Ia, Id, Ig, Ih, Ij, Ik], [Ia, Id, Ig,Ih, Ij, Il], [Ia, Id, Ig, Ih, Ij, Im], [Ia, Id, Ig, Ih, Ij, In], [Ia,Id, Ig, Ii, Ij, Ik], [Ia, Id, Ig, Ii, Ij, Il], [Ia, Id, Ig, Ii, Ij, Im],[Ia, Id, Ig, Ii, Ij, In], [Ia, Ie, If, Ih, Ij, Ik], [Ia, Ie, If, Ih, Ij,Il], [Ia, Ie, If, Ih, Ij, Im], [Ia, Ie, If, Ih, Ij, In], [Ia, Ie, If,Ii, Ij, Ik], [Ia, Ie, If, Ii, Ij, Il], [Ia, Ie, If, Ii, Ij, Im], [Ia,Ie, If, Ii, Ij, In], [Ia, Ie, Ig, Ih, Ij, Ik], [Ia, Ie, Ig, Ih, Ii, Il],[Ia, Ie, Ig, Ih, Ij, Im], [Ia, Ie, Ig, Ih, Ij, In], [Ia, Ie, Ig, Ii, Ij,Ik], [Ia, Ie, Ig, Ii, Ij, Im], [Ia, Ie, Ig, Ii, Ij, Im], [Ia, Ie, Ig,Ii, Ij, In], [Ib, Id, If, Ih, Ij, Ik], [Ib, Id, If, Ih, Ii, Il], [Ib,Id, If, Ih, Ij, Im], [Ib, Id, If, Ih, Ij, In], [Ib, Id, If, Ii, Ij, Ik],[Ib, Id, If, Ii, Ij, Il], [Ib, Id, If, Ii, Ij, Im], [Ib, Id, If, Ii, Ij,In], [Ib, Id, Ig, Ih, Ij, Ik], [Ib, Id, Ig, Ih, Ij, Il], [Ib, Id, Ig,Ih, Ij, Im], [Ib, Id, Ig, Ih, Ii, In], [Ib, Id, Ig, Ii, Ij, Ik], [Ib,Id, Ig, Ii, Ij, Il], [Ib, Id, Ig, Ii, Ij, Im], [Ib, Id, Ig, Ii, Ij, In],[Ib, Ie, If, Ih, Ij, Ik], [Ib, Ie, If, Ih, Ij, Il], [Ib, Ie, If, Ih, Ij,Im], [Ib, Ie, If, Ih, Ij, In], [Ib, Ie, If, Ii, Ij, Ik], [Ib, Ie, If,Ii, Ij, Il], [Ib, Ie, If, Ii, Ij, Im], [Ib, Ie, If, Ii, Ij, In], [Ib,Ie, Ig, Ih, Ij, Ik], [Ib, Ie, Ig, Ih, Ij, Il], [Ib, Ie, Ig, Ih, Ij, Im],[Ib, Ie, Ig, Ih, Ij, In], [Ib, Ie, Ig, Ii, Ij, Ik], [Ib, Ie, Ig, Ii, Ij,Il], [Ib, Ie, Ig, Ii, Ij, Im], [Ib, Ie, Ig, Ii, Ij, In], [Ic, Id, If,Ih, Ij, Ik], [Ic, Id, If, Ih, Ij, Il], [Ic, Id, If, Ih, Ij, Im], [Ic,Id, If, Ih, Ij, In], [Ic, Id, If, Ii, Ij, Ik], [Ic, Id, If, Ii, Ij, Il],[Ic, Id, If, Ii, Ij, Im], [Ic, Id, If, Ii, Ij, In], [Ic, Id, Ig, Ih, Ij,Ik], [Ic, Id, Ig, Ih, Ii, Il], [Ic, Id, Ig, Ih, Ij, Im], [Ic, Id, Ig,Ih, Ij, In], [Ic, Id, Ig, Ii, Ij, Ik], [Ic, Id, Ig, Ii, Ij, Il], [Ic,Id, Ig, Ii, Ij, Im], [Ic, Id, Ig, Ii, Ij, In], [Ic, Ie, If, Ih, Ij, Ik],[Ic, Ie, If, Ih, Ij, Il], [Ic, Ie, If, Ih, Ij, Im], [Ic, Ie, If, Ih, Ij,In], [Ic, Ie, If, Ii, Ij, Ik], [Ic, Ie, If, Ii, Ij, Il], [Ic, Ie, If,Ii, Ij, Im], [Ic, Ie, If, Ii, Ij, In], [Ic, Ie, Ig, Ih, Ij, Ik], [Ic,Ie, Ig, Ih, Ij, Il], [Ic, Ie, Ig, Ih, Ij, Im], [Ic, Ie, Ig, Ih, Ij, In],[Ic, Ie, Ig, Ii, Ij, Ik], [Ic, Ie, Ig, Ii, Ij, Il], [Ic, Ie, Ig, Ii, Ij,Im], [Ic, Ie, Ig, Ii, Ij, In], or [(R¹)_(n), R²-R³, R⁴, X, W]=[Ia, Io,Ih, Ij, Ik], [Ia, Io, Ih, Ij, Il], [Ia, Io, Ih, Ij, Im], [Ia, Io, Ih,Ij, In], [Ia, Io, Ii, Ij, Ik], [Ia, Io, Ii, Ij, In], [Ia, Io, Ii, Ij,Im], [Ia, Io, Ii, Ij, In], [Ia, Ip, Ih, Ij, Ik], [Ia, Ip, Ih, Ij, Il],[Ia, Ip, Ih, Ij, Im], [Ia, Ip, Ih, Ij, In], [Ia, Ip, Ii, Ij, Ik], [Ia,Io, Ii, Ij, Il], [Ia, Ip, Ii, Ij, Im], [Ia, Ip, Ii, Ij, In], [Ib, Io,Ih, Ij, Ik], [Ib, Io, Ih, Ij, Il], [Ib, Io, Ih, Ij, Im], [Ib, Io, Ih,Ij, In], [Ib, Io, Ii, Ij, Ik], [Ib, Io, Ii, Ij, Il], [Ib, Io, Ii, Ij,Im], [Ib, Io, Ii, Ij, In], [Ib, Ip, Ih, Ij, Ik], [Ib, Ip, Ih, Ij, Il],[Ib, Ip, Ih, Ij, Im], [Ib, Ip, Ih, Ij, In], [Ib, Ip, Ii, Ij, Ik], [Ib,Ip, Ii, Ij, Il], [Ib, Ip, Ii, Ij, Im], [Ib, Ip, Ii, Ij, In], [Ic, Io,Ih, Ij, Ik], [Ic, Io, Ih, Ij, Il], [Ic, Io, Ih, Ij, Im], [Ic, Io, Ih,Ij, In], [Ic, Io, Ii, Ij, Ik], [Ic, Io, Ii, Ij, Il], [Ic, Io, Ii, Ij,Im], [Ic, Io, Ii, Ij, In], [Ic, Ip, Ih, Ii, Ik], [Ic, Ip, Ih, Ij, Il],[Ic, Ip, Ih, Ij, Im], [Ic, Ip, Ih, Ij, In], [Ic, Ip, Ii, Ij, Ik], [Ic,Ip, Ii, Ij, Il], [Ic, Ip, Ii, Ij, Im], [Ic, Ip, Ii, Ij, In].

Substsituents groups (IIa) to (IIk) are shown as preferablesubstitsuent(s) groups for (R¹)_(n), R² to R⁴, and X of the compoundrepresented by the formula (II).

(R¹)_(n): (IIa) a hydrogen atom, a halogen atom, alkyl, alkoxy,optionally substituted amino, cyano, or alkoxycarbonyl, (IIb) a hydrogenatom, a halogen atom, optionally substituted amino, cyano, oralkoxycarbonyl.

R²: (IIc) C2-C4 alkyl.

R³: (IId) C2-C4 alkyl.

R⁴: (IIe) C1-C6 alkyl, (IIf) C1-C2 alkyl.

X: (IIg) an oxgen atom or a sulfur atom, (IIh) an oxgen atom, (IIi) asulfur atom.

Or, R² and R³ are taken together with the adjacent carbon atom to form(IIj) a 5 to 6 membered carbocyclic ring, (Ilk) 6 membered cyaloalkane.

Examples of preferable group ot the compound represented by the formula(II) contains [(R¹)n, R², R³, R⁴, X]=[IIa, IIc, IId, IIe IIg], [IIa,IIc, IId, IIe IIh], [IIa, IIc, IId, IIe IIi], [IIa, IIc, IId, IIf IIg],[IIa, IIc, IId, IIf IIh], [IIa, IIc, IId, IIf Ili], [IIb, IIc, IId, IIeIIg], [IIb, IIc, IId, IIe IIh], [IIb, IIc, IId, IIe IIi], [IIb, IIc,IId, IIf IIg], [IIb, IIc, IId, IIf IIh], [IIb, IIc, IId, IIf IIi], or[(R¹)_(n), R²-R³, R⁴, X]=[IIa, IIj, IIe, IIg], [IIa, IIj, IIe, IIh],[IIa, IIj, IIe, IIi], [IIa, IIj, IIf, IIg], [IIa, IIj, IIf, IIh], [IIa,IIj, IIf, IIi], [IIa, IIk, IIe, IIg], [IIa, IIk, IIe, IIh], [IIa, IIk,IIe, IIi], [IIa, IIk, IIf, IIg], [IIa, IIk, IIf, IIh], [IIa, IIk, IIf,IIi], [IIb, IIj, IIe, IIg], [IIb, IIj, IIe, IIh], [IIb, IIj, IIe, IIi],[IIb, IIj, IIf, IIg], [IIb, IIj, IIf, IIh]; [IIb, IIj, IIf, IIi], [IIb,IIk, IIe, IIg], [IIb, IIk, IIe, IIh], [IIb, IIk, IIe, IIi], [IIb, IIk,IIf, IIg], [IIb, IIk, IIf, IIh], [IIb, IIk, IIf, IIi].

Substsituents groups (IIIa) to (IIIn) are shown as preferablesubstitsuent(s) groups for (R¹)_(n), R² to R⁴, and X of the compoundrepresented by the formula (III).

(R¹)_(n): (IIIa) a hydrogen atom, a halogen atom, alkyl, alkoxy,optionally substituted amino, cyano, or alkoxycarbonyl, (IIIb) ahydrogen atom, a halogen atom, optionally substituted amino, cyano, oralkoxycarbonyl.

R²: (IIIc) C2-C4 alkyl.

R³: (IIId) C2-C4 alkyl.

R⁴: (IIIe) C1-C6 alkyl, (IIIf) C1-C2 alkyl.

X: (IIg) an oxgen atom or a sulfur atom, (IIIh) an oxgen atom, (IIIi) asulfur atom.

R² and R³ are taken together with the adjacent carbon atom to form(IIIj) a 5 to 6 membered cyaloalkane, (IIIk) 6 membered cyaloalkane.

Or, Z: (IIIl) —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—, (IIIm) —CH₂CH₂CH₂CH₂—,(IIIn) —OCH₂CH₂O—.

Examples of preferable group ot the compound represented by the formula(III) contains [(R¹)_(n), R², R₃, R⁴, X, Z]=[IIIa, IIIc, IIId, IIIeIIIg, IIIl], [IIIa, IIIc, IIId, IIIe, IIIg, IIIm], [IIIa, IIIc, IIId,IIIe, IIIg, IIIn], [IIIa, IIIc, IIId, IIIe, IIIh, IIIl], [IIIa, IIIc,IIId, IIIe, IIIh, IIIm], [IIIa, IIIc, IIId, IIIe, IIIh, IIIn], [IIIa,IIIc, IIId, IIIe, IIIi, IIIl], [IIIa, IIIc, IIId, IIIe, IIIi, IIIm],[IIIa, IIIc, IIId, IIIe, IIIi, IIIn], [IIIa, IIIc, IIId, IIIf, IIIg,IIIl], [IIIa, IIIc, IIId, IIIf, IIIg, IIIm], [IIIa, IIIc, IIId, IIIf,IIIg, IIIn], [IIIa, IIIc, IIId, IIIf, IIIh, IIIl], [IIIa, IIIc, IIId,IIIf, IIIh, IIIm], [IIIa, IIIc, IIId, IIIf, IIIh, IIIn], [IIIa, IIIc,IIId, IIIf, IIIi, IIIl], [IIIa, IIIc, IIId, IIIf, IIIi, IIIm], [IIIa,IIIc, IIId, IIIf, IIIi, IIIn], [IIIb, IIIc, IIId, IIIe, IIIg, IIIl],[IIIb, IIIc, IIId, IIIe, IIIg, IIIm], [IIIb, IIIc, IIId, IIIe, IIIg,IIIn], [IIIb, IIIc, IIId, IIIe, IIIh, IIIl], [IIIb, IIIc, IIId, IIIe,IIIh, IIIm], [IIIb, IIIc, IIId, IIIe, IIIh, IIIn], [IIIb, IIIc, IIId,IIIe, IIIi, IIIl], [IIIb, IIIc, IIId, IIIe, IIIi, IIIm], [IIIb, IIIc,IIId, IIIe, IIIi, IIIn], [IIIb, IIIc, IIId, IIIf, IIIg, IIIl], [IIIb,IIIc, IIId, IIIf, IIIg, IIIm], [IIIb, IIIc, IIId, IIIf, IIIg, IIIn],[IIIb, IIIc, IIId, IIIf, IIIh, IIIl], [IIIb, IIIc, IIId, IIIf, IIIh,IIIm], [IIIb, IIIc, IIId, IIIf, IIIh, IIIn], [IIIb, IIIc, IIId, IIIf,IIIi, IIIl], [IIIb, IIIc, IIId, IIIf, IIIi, IIIm], [IIIb, IIIc, IIId,IIIf, IIIi, IIIn], or [(R¹)_(n), R²-R³, R⁴, X, Z]=[IIIa, IIIj, IIIe,IIIg, IIIl], [IIIa, IIIj, IIIe, IIIg, IIIm], [IIIa, IIIj, IIIe, IIIg,IIIn], [IIIa, IIIj, IIIe, IIIh, IIIl], [IIIa, IIIj, IIIe, IIIh , IIIm],[IIIa, IIIj, IIIe, IIIh, IIIn], [IIIa, IIIj, IIIe, IIIi, IIIl], [IIIa,IIIj, IIIi, IIIm], [IIIa, IIIj, IIIe, IIIi, IIIn], [IIIa, IIIj, IIIf,IIIg, IIIm], [IIIa, IIIj, IIIf, IIIg, IIIn], [IIIa, IIIj, IIIf, IIIh,IIIl], [IIIa, IIIj, IIIf, IIIh, IIIm], [IIIa, IIIj, IIIf, IIIh, IIIn],[IIIa, IIIj, IIIf, IIIi, IIIl], [IIIa, IIIj, IIIf, IIIi, IIIm], [IIIa,IIIj, IIIf, IIIi, IIIn], [IIIa, IIIk, IIIe, IIIg, IIIl], [IIIa, IIIk,IIIe, IIIg, IIIm], [IIIa, IIIk, IIIe, IIIg, IIIn], [IIIa, IIIk, IIIe,IIIh, IIIl], [IIIa, IIIk, IIIe, IIIh, IIIm], [IIIa, IIIk, IIIe, IIIh,IIIn], [IIIa, IIIk, IIIe, IIIl], [IIIa, IIIk, IIIe, IIIi, IIIm], [IIIa,IIIk, IIIe, IIIi, IIIn], [IIIa, IIIk, IIIf, IIIg, IIIl], [IIIa, IIIk,IIIf, IIIg, IIIm], [IIIa, IIIk, IIIf, IIIg, IIIn], [IIIa, IIIk, IIIf,IIIh, IIIl], [IIIa, IIIk, IIIf, IIIh, IIIm], [IIIa, IIIk, IIIf, IIIh,IIIn], [IIIa, IIIk, IIIf, IIIi, IIIl], [IIIa, IIIk, IIIf, IIIi, IIIm],[IIIa, IIIk, IIIf, IIIi, IIIn], [IIIb, IIIj, IIIe, IIIg, IIIl], [IIIb,IIIj, IIIe, IIIg, IIIm], [IIIb, IIIj, IIIe, IIIg, IIIn], [IIIb, IIIj,IIIe, IIIh, IIIl], [IIIb, IIIj, IIIe, IIIh, IIIm], [IIIb, IIIj, IIIe,IIIh, IIIn], [IIIb, IIIj, IIIe, IIIi, IIIl], [IIIb, IIIj, IIIe, IIIi,IIIm], [IIIb, IIIj, IIIe, IIIi, IIIn], [IIIb, IIIj, IIIf, IIIg, IIIl],[IIIb, IIIj, IIIf, IIIg, IIIm], [IIIb, IIIj, IIIf, IIIg, IIIn], [IIIb,IIIj, IIIf, IIIh, IIIl], [IIIb, IIIj, IIIf, IIIh, IIIm], [IIIb, IIIj,IIIf, IIIh, IIIn], [IIIb, IIIj, IIIf, IIIi, IIIl], [IIIb, IIIj, IIIf,IIIi, IIIm], [IIIb, IIIj, IIIf, IIIi, IIIn], [IIIb, IIIk, IIIe, IIIg,IIIl], [IIIb, IIIk, IIIe, IIIg, IIIm], [IIIb, IIIk, IIIe, IIIg, IIIn],[IIIb, IIIk, IIIe, IIIh, IIIl], [IIIb, IIIk, IIIe, IIIh, IIIm], [IIIb,IIIk, IIIe, IIIh, IIIn], [IIIb, IIIk, IIIe, IIIi, IIIl], [IIIb, IIIk,IIIe, IIIi, IIIm], [IIIb, IIIk, IIIe, IIIi, IIIn], [IIIb, IIIk, IIIf,IIIg, IIIl], [IIIb, IIIk, IIIf, IIIg, IIIm], [IIIb, IIIk, IIIf, IIIg,IIIn], [IIIb, IIIk, IIIf, IIIh, IIIl], [IIIb, IIIk, IIIf, IIIh, IIIm],[IIIb, IIIk, IIIf, IIIh, IIIn], [IIIb, IIIk, IIIf, IIIi, IIIl], [IIIb,IIIk, IIIf, IIIi, IIIm], [IIIb, IIIk, IIIf, IIIi, IIIn].

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present Invention can be synthesized by thefollowing routes

wherein R¹ is, the same or different, alkyl, alkoxy, alkylthio,optionally substituted amino, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted aralkyloxy, cycloalkyl, ahalogen atom, hydroxy, nitro, haloalkyl, haloalkoxy, optionallysubstituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl,alkylsulfonyl, alkoxylalkyl, alkylthioalkyl, optionally substitutedaminoalkyl, alkoxyiminoalkyl, alkoxyalkoxy, alkylthioalkoxy,alkoxycarbonylalkoxy, carboxyalkoxy, alkylsulfonyloxy, optionallysubstituted heteroaryl, an optionally substituted non-aromaticheterocyclic group, cyano, cyanoalkoxy, or a group of the formula:—C(═O)—R^(H) wherein R^(H) is a hydrogen atom, alkyl, optionallysubstituted aryl, or an optionally substituted non-aromatic heterocyclicgroup;

R² and R³ are the same or different and each is C2-C4 alkyl, C2-C4alkenyl, C1-C4 alkoxyC1-C4 alkyl, optionally substituted aminoC1-C4alkyl, or C3-C6 cycloalkylC1-C4 alkyl; or

R² and R³ are taken together with the adjacent carbon atom may form anoptionally substituted 5 to 8 membered non-aromatic carbocyclic ring oran optionally substituted 5 to 8 membered non-aromatic heterocyclicring;

R⁴ is C1-C6 alkyl, hydroxyalkyl may be protected by the protectinggroup, optionally substituted aminoalkyl, or C1-C6 alkoxyC1-C6 alkyl;

R⁵ is, same or different, alkyl, alkoxy, alkylthio, optionallysubstituted amino, optionally substituted amino may be protected by theprotecting group, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted aralkyloxy, cycloalkyl, a halogen atom,hydroxy protected by the protecting group, nitro, haloalkyl, haloalkoxy,optionally substituted carbamoyl, carboxy protected by the protectinggroup, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxylalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyiminoalkyl,alkoxyalkoxy, alkylthioalkoxy, alkoxycarbonylalkoxy, carboxyalkoxy,alkylsulfonyloxy, optionally substituted heteroaryl, an optionallysubstituted non-aromatic heterocyclic group, cyano, cyanoalkoxy, or agroup of the formula: —C(═O)—R^(H) wherein R^(H) is a hydrogen atom,alkyl, optionally substituted aryl, or an optionally substitutednon-aromatic heterocyclic group;

X is an oxgen atom or a sulfur atom;

A is the group of the formula:

W is C2-C6 alkylene which contain a optionally substituted heteroatom(s)or C2-C4 alkenylene which contain an optionally substitutedheteroatom(s);

n is an integer of 0 to 7.

Step 1

This is a process for producing a compound of the formula (V) whichcomprises converting an amino group of a compound of the formula (IV) toisothiocyanic acid ester (isothiocyanate).

A method for converting an amino group to isothio cyanic acid ester(isothiocyanate) includes the following methods; (1) a method whichcomprises reacting the starting compound with carbon disulfide in thepresence of a base such as ammonia (NH₃, NH₄OH), triethylamine (Et₃N)and reacting the obtained dithiocarbamate with ethyl chlorocarboxylate(ClCO₂Et) and triethylamine (Et₃N), (2) a method which comprisesreacting the above dithiocarbamate with acid metalate such as leadnitrate or the like, (3) a method of reacting thiophosgene (CSCl₂) and(4) a method of reacting thiocarbonyldlimidazole or the like.

In the above (1), a base (1.0 to 1.5 mole equivalent) and carbondisulfide (1.0 to 1.5 mole equivalent) are added to a solution of acompound of the formula (III) in an aprotic solvent (e.g., diethylether,tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane,chloroform) and the mixture is stirred for 0.5 to 10 hours. After that,ethyl chlorocarboxylate (1.0 to 1.5 mole equivalent) and triethylamine(1.0 to 1.5 mole equivalent) are added thereto and the mixture isstirred in the same solvent for 0.5 to 10 hours. The reactiontemperature is preferably 0 to 100° C., especially 0° C. to roomtemperature.

In the above (3), thiophosgene (1.0 to 1.5 mole equivalent) is added toa solution of the compound of the formula (IV) in an aprotic solvent(e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene,toluene, dichloromethane, chloroform) and stirred for 0.5 to 10 hours.The reaction temperature is preferably 0 to 100° C., especially 0° C. toroom temperature.

In the above (4), thiocarbonyldiimidazole (1.0 to 1.5 mole equivalent)is added to a solution of the compound of the formula (IV) in an aproticsolvent (e.g., diethylether, tetrahydrofuran, dimethylformamide,benzene, toluene, dichloromethane, chloroform) and stirred for 0.5 to 10hours. The reaction temperature is preferably 0 to 100° C., especially0° C. to room temperature.

1-Aminonaphthalene,1-amino-2-fluoronaphthalene,1-amino-3-fluoronaphthalene,1-amino-4-fluoronaphthalene, 1-amino-5-fluoronaphthalene,1-amino-6-fluoronaphthalene, 1-amino-7-fluoronaphthalene,1-amino-8-fluoronaphthalene, 1-amino-2-chloronaphthalene,1-amino-3-chloronaphthalene, 1-amino-4-chloronaphthalene,1-amino-5-chloronaphthalene, 1-amino-6-chloronaphthalene,1-amino-7-chloronaphthalene, 1-amino-8-chloronaphthalene,1-amino-2-bromonaphthalene, 1-amino 3-bromonaphthalene,1-amino-4-bromonaphthalene, 1-amino-5-bromonaphthalene,1-amino-6-bromonaphthalene, 1-amino-7-bromonaphthalene,1-amino-8-bromonaphthalene, 1-amino-2-methylnaphthalene,1-amino-3-methylnaphthalene, 1-amino-4-methylnaphthalene,1-amino-5-methylnaphthalene, 1-amino-6-methylnaphthalene,1-amino-7-methylnaphthalene, 1-amino-8-methylnaphthalene,1-amino-2-methoxynaphthalene, 1-amino-3-methoxynaphthalene,1-amino-4-methoxynaphthalene, 1-amino-5-methoxynaphthalene,1-amino-6-methoxynaphthalene, 1-amino-7-methoxynaphthalene,1-amino-8-methoxynaphthalene,1-amino-2-N,N-dimethylaminonaphthalene,1-amino-3-N,N-dimethylaminonaphthalene,1-amino-4-N,N-dimethylaminonaphthalene,1-amino-5-N,N-dimethylaminonaphthalene,1-amino-6-N,N-dimethylaminonaphthalene,1-amino-7-N,N-dimethylaminonaphthalene,1-amino-8-N,N-dimethylaminonaphthalene, 1-amino-2-benzyloxynaphthalene,1-amino-3-benzyloxynaphthalene, 1-amino-4-benzyloxynaphthalene,1-amino-5-benzyloxynaphthalene, 1-amino-6-benzyloxynaphthalene,1-amino-7-benzyloxynaphthalene, 1-amino-8-benzyloxynaphthalene,1-amino4-(2-pyridyl)naphthalene, 1-amino-2-trifluoromethylnaphthalene,1-amino-3-trifluoromethylnaphthalene, 1-amino-4-trifluoromethylnaphthalene, 1-amino -5-trifluoromethylnaphthalene,1-amino-6-trifluoromethylnaphthalene,1-amino-7-trifluoromethylnaphthalene,1-amino-8-trifluoromethylnaphthalene,1-amino-2-trifluoromethoxynaphthalene,1-amino-3-trifluoromethoxynaphthalene,1-amino-4-trifluoromethoxynaphthalene, 1-amino-5-trifluoromethoxynaphthalene, 1-amino-6-trifluoromethoxynaphthalene,1-amino-7-trifluoromethoxynaphthalene,1-amino-8-trifluoromethoxynaphthalene, 1-amino-2-cyanonaphthalene,1-amino-3-cyanonaphthalene, 1-amino-4-cyanonaphthalene,1-amino-5-cyanonaphthalene, 1-amino-6-cyanonaphthalene,1-amino-7-cyanonaphthalene, 1-amino-8-cyanonaphthalene and the like areexemplified as the compound of the formula (IV).

Step 2

This is a process for producing a compound of the formula (VI) whichcomprises reacting an isothiocyanate of the compound of the formula (V)with NH₂—CH₂C(R²R³)CH₂—OH wherein R² and R³ are defined as above.

This process can be carried out in an aprotic solvent (e.g.,diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene,dichloromethane, chloroform).

The reaction temperature is preferably 0 to 100° C., especially 0° C. toroom temperature. The reaction time is 0.5 to 10 hours.

The amount of NH₂—CH₂C(R²R³)CH₂—OH is 1.0 to 1.5 mole equivalent to thatof the compound of the formula (IV).

3-Amino-2,2-diethylpropanol, 3-amino-2,2-di(n-propyl)propanol,3-amino-2,2-diisopropylpropanol, 3-amino-2,2-di(n-butyl)propanol,(1-aminomethyl-1-cyclopentyl)metahnol,(1-aminomethyl-1-cyclohexyl)methanol, (1-aminomethyl-1-cycloheptyl)methanol, (1-aminomethyl-1-cyclooctyl)methanol,(4-aminomethyl-4-tetrapyranyl)methanol,(4-aminomethyl-N-methyl-4-piperidinyl)methanol, and the like areexemplified as NH₂—CH₂C(R²R³)CH₂—OH.

Step 3

This is a process for producing a compound of the formula (VII) whichcomprises the cyclization of the compound of the formula (VI).

A method of the cyclization includes (1) a method which comprisesreacting with carbon tetrachloride and triphenylphosphine (Ph₃P), andthen with potassium carbonate, (2) a method which comprises reactingwith hydrochloric acid.

In the above (1), the reaction can be carried out in an aprotic solvent(e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene,toluene, dichloromethane, chloroform) with stirring for 0.5 to 5 hoursat 0° C. to room temperature. The amount of carbon tetrachloride andtriphenylphosphine (Ph₃P) are 1.0 to 1.5 mole equivalent to that of thecompound (V).

In the above (2), the reaction can be carried out in concentratedhydrochloric acid with refluxing for 0.5 to 10 hours.

Step 4

This is a process for producing a compound of the formula (Ib) whichcomprises introducing —C(═X)—SR⁴ to a compound of the formula (Ib).

This process can be carried out by reacting with a compound of theformula: Hal—C(═X)—SR⁴ wherein R⁴ and X are as defined above and Hal isa halogen atom in the presence of a base (e.g., triethylamine, pyridine,N,N-dimethylaminopyridine). This process can be carried out undergenerally known conditions of N-acylation. For example, the reaction canbe carried out in an aprotic solvent (e.g., diethylether,tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane,chloroform) with stirring at 0 to 100° C. for 0.5 to 10 hours.

Moreover, it can be prepared by reacting with carbon dioxide (CS₂) inthe presence of a base (e.g., sodium hydride), and reacting with alkylhalide (e.g., methyl iodide, ethyl iodide) or alkoxyalkyl halide (e.g.,chloromethyl methyl ether). The reaction can be carried out in anaprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide,benzene, toluene, dichloromethane, chloroform) with stirring at 0° C. toroom temperature.

Step 5

This is a process for producing a compound of the formula (Ia) whichcomprises a) deprotection or b) deprotection and alkylation wherein R⁵has the group protected with protecting group.

Deprotection can be carried out by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) or thelike.

Alkylation can be carried out by reacting with alkyl halide (e.g.,methyl iodide, ethyl iodide) or (alkoxycarbonyl)alkyl halide (e.g.,t-butoxycarbonylmethy brmide) in the presence of a base (e.g., sodiumhydride). The reaction can be carried out in an aprotic solvent (e.g.,diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene,dichloromethane, chloroform) with stirring at 0° C. to room temperature.

When A is benzthiazol-4-yl in the formula (I), it can be synthesized bythe following steps. Each step can be used by similar method describedabove each step in preparating the formula (Ib) from the formula (IV).

wherein R², R₃, R⁴, R⁵, and n are defined as above.

A prodrug is a derivative which is converted to a pharmaceuticallyactive compound of the present invention under a physiologicalcondition. Method for the selection and process of an appropriateprodrug derivative are described in the literature such as Design ofProdrugs, Elsevier, Amsterdam 1985.

A prodrug of the present invention can be prepared by introducing aleaving group to substituents on ring A which are substitutable (e.g.,amino, hydroxy). Examples of a prodrug derived form a compound having anamino group includes carbamate derivatives (e.g., methylcarbamate,cyclopropylmethylcarbamate, t-butylcarbamate, benzylcarbamate), amidederivatives (e.g., formamide, acetamide), N-alkyl derivative (e.g.,N-allylamine, N-methoxymethylamine) or the like. Examples of a prodrugderived form a compound having hydroxy group include ether derivatives(methoxymethylether, methoxyethoxymethylether), ester derivatives (e.g.,acetate, pivaloate, benzoate) or the like.

Examples of a pharmaceutically acceptable salt include basic salts(e.g., alkali metal salts such as sodium or potassium salts;alkaline-earth metal salts such as calcium or magnesium salts; ammoniumsalts; aliphatic amine salts such as trimethylamine, triethylamine,dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine orprocaine salts; aralkyl amine salts such as N,N-dibenzylethylenediaminesalts; heterocyclic aromatic amine salts such as pyridine salts,picoline salts, quinoline salts or isoquinoline salts; quaternaryammonium salts such as tetramethylammonium salts, tetraethylammoniumsalts, benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts such as argininesalts or lysine salts). Acid addition salts include, for example,mineral acid salts such as hydrochlorides salts, sulfates salts, nitratesalts, phosphates salts, carbonates salts, hydrogen carbonates salts orperchlorates salts; organic acid salts such as acetates, propionates,lactates, maleates, fumarates, tartrates, malates, succinates, orascorbates; sulfonates such as methanesulfonates, isethionates,benzenesulfonates, or p-toluenesulfonates; and acidic amino acid saltssuch as aspartates or glutamates.

A solvate includes a solvate of the compound of the formula (I), (II),or (III) a prodrug of itself or a pharmaceutically acceptable saltthereof, for example, monosolvate, disolvate, monohydrate, dihydrate orthe like.

The compound of the present invention can be used for treating orpreventing diseases associated with a cannabinoid receptor agonist. Forexample, in nature 1993, 3(65), 61-65 it discloses that a cannabinoidreceptor agonist has an anti-inflammatory activity and analgesicactivity, in Journal of Cannabis Therapeutics 2000, 2(1), 59-71 itdiscloses that a cannabinoid receptor agonist has a bronchiectasisactivity, and in WO 03/035109 it discloses that a cannabinoid receptoragonist has an antipruritics activity.

Therefore, the compound of the present invention can be used as anantiinflammatory agent, an antiallergic agent, an analgesics, an algesicagent (e.g., an algesic agent of nociceptivity, a neurogenic algesicagent, a psychogenic algesic agent, an acute algesic agent, a chronicalgesic agent), an immunodeficiency disease treating agent, animmunosuppressive agent, an immunomodulating agent, an autoimmunedisease treating agent, chronic rheumatoid arthritis treating agent,multiple sclerosis treating agent, an inhibitor for inflammatory cellarinfiltration in the respiratory tract, an inhibitor forhyperirritability in the respiratory tract, a muciparous inhibitor,abronchodilator an antipruritics, or the like.

When using a compound of the present invention in treatment, it can beformulated into ordinary formulations for oral and parenteraladministration. A pharmaceutical composition containing a compound ofthe present invention can be in the form for oral and parenteraladministration. Specifically, it can be formulated into formulations fororal administration such as tablets, capsules, granules, powders, syrup,and the like; those for parenteral administration such as injectablesolution or suspension for intravenous, intramuscular or subcutaneousinjection, inhalant, eye drops, nasal drops, suppositories, orpercutaneous formulations such as ointment.

In preparing the formulations, carriers, excipients, solvents and basesknown to one ordinary skilled in the art may be used. Tablets areprepared by compressing or formulating an active ingredient togetherwith auxiliary components. Examples of usable auxiliary componentsinclude pharmaceutically acceptable excipients such as binders (e.g.,cornstarch), fillers (e.g., lactose, microcrystalline cellulose),disintegrates (e.g., starch sodium glycolate) or lubricants (e.g.,magnesium stearate). Tablets may be coated appropriately. In the case ofliquid formulations such as syrups, solutions or suspensions, they maycontain suspending agents (e.g., methyl cellulose), emulsifiers (e.g.,lecithin), preservatives and the like. In the case of injectableformulations, it may be in the form of solution or suspension, or oilyor aqueous emulsion, which may contain suspension-stabilizing agent ordispensing agent, and the like. In the case of an inhalant, it isformulated into a liquid formulation applicable to an inhaler. In thecase of eye drops, it is formulated into a solution or a suspension.

Although an appropriate dosage of the present compound varies dependingon the administration route, age, body weight, sex, or conditions of thepatient, and the kind of drug(s) used together, if any, and should bedetermined by the physician in the end, in the case of oraladministration, the daily dosage can generally be between about 0.01-100mg, preferably about 0.01-10 mg, more preferably about 0.1-10 mg, per kgbody weight. In the case of parenteral administration, the daily dosagecan generally be between about 0.001-100 mg, preferably about 0.001-1mg, more preferably about 0.01-1 mg, per kg body weight. The dailydosage can be administered in 1-4 divisions.

The following Examples are provided to further illustrate the presentinvention and are not to be construed as limiting the scope.

The meaning of each abbreviation are shown as follows.

-   Me: methyl,-   Et: ethyl,-   Pr: propyl,-   i-Pr: isopropyl,-   t-Bu: t-butyl,-   Ph: phenyl,-   Bn: benzyl,-   DMF: N,N-dimethylformamide

EXAMPLES Example 1 Synthesis of3-[(methylthio)thiocarbonyl]-2-(1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-23)

To the mixture of 1-naphthylamine (21.48 g), triethylamine (33.39 g),and dichloromethane (250 mL) was added a dicholomethane (50 mL) solutionof thiophosgen (18.97 g) at bleow 20° C. over 30 minutes, and themixture was stirred at room temperature. The reaction mixture was addedinto ice-water (1000 mL), extracted with diethyl ether (1000 mL). Theextract was washed two times with brine (1000 mL), dried over anhydrousmagnesium sulfate, evaporated under reduced pressure to obtain crude(1-naphthyl)isothiocyanate.

To a dichlorometane (100 mL) solution of the obtained crude(1-naphthyl)isothiocyanato was added a dichlorometane (50 mL) solutionof 3-amino-2,2-pentamethylenepropanol (27.93 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 h. To the reactionmixture was added water (1000 mL), and the reaction mixture wasextracted with dichlorometane (400 mL). The extract was washed withbrine (500 mL), dried over anhydrous magnesium sulfate, evaporated underreduced pressure to obtain crudeN-(1-naphthyl)-N′-(3-hydroxy-2,2-pentamethylenepropyl)thiourea.

To a mixture of the obtained crude N-(1-naphthyl)-N′-(3-hydroxy-2,2-pentamethylenepropyl)thiourea,triphenylphosphine (59.02 g), and acetonitrile (300 mL) was added carbontetrachloride (69.22 g) under ice-cooling over 20 minutes. After thereaction mixtuer was stirred at room temperature for 1 h, potassiumcarbonate (31.10 g) was added to the reaction mixture under ice-cooling,and the reaction mixture was stirred at room temperature for 1 h. To thereaction mixture were added ic-water (400 mL) and ethyl acetate (300mL), and the reaction mixture is crystalized. The resulting crystalswere filtered to obtain 2-(1-naphthyl)-5,5-pentamethylene-1,3-thiazine(33.61 g, 72%) as colorless crystals. ¹H—NMR (δ ppm TMS/CDCl₃) 1.40-1.64(10H, m), 2.71 (2H, s), 3.17 (2H, s), 5.73 (1H, brs), 7.01 (1H, d,J=6.9), 7.35-7.47 (3H, m), 7.55 (1H, d, J=8.3), 7.81 (1H, m), 8.01 (1H,m).

To a mixture of 2-(1-naphthyl)-5,5-pentamethylene-1,3-thiazine (33.61g), carbon disulfide (11.42 g), and FDMF (200 mL) was added 60% sodiumhydride (6.0 g) under ice-cooling over 5 minutes. After the reactionmixtuer was stirred at 0° C. for 30 minutes, methyl iodide (21.29 g) wasadded to the reaction mixture under ice-cooling over 20 minutes, and thereaction mixture was stirred at 0 for 1 h. To the reaction mixture wereadded ic-water (800 mL), and the reaction was extracted withdiethylether (500 mL). The extract was washed with brine (1000 mL),dried over anhydrous magnesium sulfate, evaporated under reducedpressure. The obtained crude product was recrystalized fromacetone/2-propanol to obtain3-[(methylthio)thiocarbonyl]-2-(1-naphthyl)-5,5-pentamethylene-1,3-thiazine(I-23: 26.13 g, 65%) as yellow crystals.

Example 2 Synthesis of3-[(methylthio)thiocarbonyl]-2-(7-hydroxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-62)

To a anisole (9 mL) of3-[(methylthio)thiocarbonyl]-2-(7-benzyloxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-61: 0.91 g) was added aluminium chloride (0.36 g) under ice-cooling,and the reaction mixtuer was stirred at 0° C. for 30 minutes. Thereaction mixture was poured into a half-saturated sodiumhydrogencarbonate aqueous solution (150 mL), and the reaction wasextracted with diethylether (150 mL). The extract was washed with brine(150 mL), dried over anhydrous magnesium sulfate, evaporated underreduced pressure. The obtained residue was purified by thecolumn-chromatography on silica gel (hexane/ethyl acetate),recrystalized from diisopropyl ether/hexane to obtain3-[(methylthio)thiocarbonyl]-2-(7-hydroxy-1-naphthyl)-5,5-pentamethylene-1,3-thiazine (I-62: 0.31 g, 41%) as yellow crystals.

Example 3 Synthesis of3-[(methylthio)thiocarbonyl]-2-(7-t-butoxycarbonylmethoxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-89)

To a suspension of3-[(methylthio)thiocarbonyl]-2-(7-hydroxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-62: 0.21 g), potassium carbonate (0.14 g), and DMF (2 mL) was addedt-butyl bromoacetate (0.20 g), and the reaction mixtuer was stirred atroom temperature for 1 h. The reaction mixture was poured into ice-water(80 mL), and the reaction was extracted with diethylether (100 mL). Theextract was washed with brine (80 mL), dried over anhydrous magnesiumsulfate, evaporated under reduced pressure. The obtained residue waspurified by the column-chromatography on silica gel (hexane/ethylacetate), recrystalized from ethyl acetate/hexane to obtain3-[(methylthio)thiocarbonyl]-2-(7-t-butoxycarbonylmethoxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(1-89: 0.22 g, 83%) as yellow crystals.

Example 4 Synthesis of3-[(methylthio)thiocarbonyl]-2-(7-carboxymethoxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-90)

To a dichloromethane (2 mL) solution of3-[(methylthio)thiocarbonyl]-2-(t-butoxycarbonylmethoxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-89: 0.21 g), was added trifluoroacetic acid (1 mL) under ice-cooling,and the reaction mixtuer was stirred at room temperature for 2 h. To thereaction mixture was added toluene (5 mL), and the mixture wasevaporated under reduced pressure. The obtained residue wasrecrystalized from ethyl acetate/diisopropyl ether to obtain3-[(methylthio)thiocarbonyl]-2-(7-carboxymethoxy-1-naphthylimino)-5,5-pentamethylene-1,3-thiazine(I-90: 0.12 g, 63%) as yellow crystals.

Example 5 Synthesis of3-[(methylthio)thiocarbonyl]-2-(4-dimethylamino-1-naphthylimino)-5,5-diisopropyl-1,3-thiazinehydrochloric acid salt (I-152)

To a diethyl ether (5 mL) solution of3-[(methylthio)thiocarbonyl]-2-(4-dimethylamino-1-naphthylimino)-5,5-diisopropyl-1,3-thiazine(I-43: 0.15 g), was added 4N dioxane solution of hydrochloric acid (0.23mL), and the reaction mixtuer was stirred at room temperature for 0.5 h.The resulting crystals were filterd to obtain3-[(methylthio)thiocarbonyl]-2-(4-dimethylamino-1-naphthylimino)-5,5-diisopropyl-1,3-thiazinehydrochloric acid salt (I-152: 0.14 g, 94%) as yellow crystals.

The compounds I-1 to I-22, I-24 to I-61, I-63 to I-88, and I-91 to I-151were synthesized by the similar method described above. Structures andphysical data of the Compounds I-1 to I-151 were shown in Tables 1 to16. TABLE 1

No.

R²     R³ R⁴ X I-1 I-2 I-3 I-4 I-5

—(CH₂)₅——(CH₂)₄—Et    Et Pr    Pr Pr     Pr Me Me Me Me Me S S S S O I-6I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15

—(CH₂)₅——(CH₂)₅—Et    Et —(CH₂)₄—i-Pr   i-Pr Et    Et Allyl  Allyl—(CH₂)₄—i-Pr   i-Pr Allyl  Allyl Me Me Me Me Me Me Me Me Me Me S O S S SO S O O O I-16 I-17 I-18 I-19 I-20

Et    Et —(CH₂)₄——(CH₂)₅——(CH₂)₄——(CH₂)₅— Me Me Me Me Me S S S O O

TABLE 2

No. (R¹)_(n) R² R³ R⁴ X I-21 H —(CH₂)₄— Me S I-22 H Pr Pr Me S I-23 H—(CH₂)₅— Me S I-24 H Et Et Me S I-25 H Pr Pr Me O I-26 H —(CH₂)₅— Me OI-27 H iPr i-Pr Me S I-28 H Allyl Allyl Me S I-29 H i-Pr i-Pr Me O I-302-Me —(CH₂)₄— Me S I-31 2-Me —(CH₂)₅— Me S I-32 4-Cl —(CH₂)₄— Me S I-334-Cl —(CH₂)₅— Me S I-34 4-Cl —(CH₂)₄— Me O I-35 4-Cl —(CH₂)₅— Me O I-362-OMe —(CH₂)₄— Me S I-37 2-OMe —(CH₂)₅— Me S I-38 2-OMe i-Pr i-Pr Me SI-39 4-OMe —(CH₂)₅— Me S I-40 4-OMe i-Pr i-Pr Me S I-41 4-Br —(CH₂)₅— MeS I-42 4-(2-Pyridyl) —(CH₂)₅— Me S I-43 4-N(Me)₂ i-Pr i-Pr Me S I-444-N(Me)₂ —(CH₂)₄— Me S I-45 4-N(Me)₂ —(CH₂)₅— Me S I-46 H—(CH₂)₂O(CH₂)₂— Me S I-47 H —(CH₂)₂O(CH₂)₂— Me O I-48 7-OMe —(CH₂)₄— MeS I-49 7-OMe —(CH₂)₅— Me S I-50 7-OMe i-Pr i-Pr Me S I-51 H—(CH₂)₂NMe(CH₂)₂— Me S I-52 H —(CH₂)₅— Et S I-53 H i-Pr i-Pr Et S I-54 H—(CH₂)₅— CH₂OMe S I-55 H i-Pr i-Pr CH₂OMe S I-56 H —(CH₂)₅— Et O I-57 Hi-Pr i-Pr Et O I-58 6-OMe —(CH₂)₄— Me S I-59 6-OMe —(CH₂)₅— Me S I-606-OMe i-Pr i-Pr Me S

TABLE 3

No. (R¹)_(n) R² R³ R⁴ X I-61 7-OBn —(CH₂)₅— Me S I-62 7-OH —(CH₂)₅— Me SI-63 5-OMe —(CH₂)₄— Me S I-64 5-OMe —(CH₂)₅— Me S I-65 5-OMe i-Pr i-PrMe S I-66 5-OMe —(CH₂)₄— Me O I-67 5-OMe —(CH₂)₅— Me O I-68 5-OMe i-Pri-Pr Me O I-69 6-OBn —(CH₂)₅— Me S I-70 6-OBn i-Pr i-Pr Me S I-71 6-OH—(CH₂)₅— Me S I-72 6-OSO₂Me —(CH₂)₅— Me S I-73 6-OCH₂CO₂-t-Bu —(CH₂)₅—Me S I-74 6-OCH₂CO₂H —(CH₂)₅— Me S I-75 6-OH i-Pr i-Pr Me S I-766-OSO₂Me i-Pr i-Pr Me S I-77 6-OCH₂CO₂-t-Bu i-Pr i-Pr Me S I-786-OCH₂CO₂H i-Pr i-Pr Me S I-79 5-OBn —(CH₂)₅— Me S I-80 5-OBn i-Pr i-PrMe S I-81 5-OH —(CH₂)₅— Me S I-82 5-OH i-Pr i-Pr Me S I-83 5-OSO₂Me—(CH₂)₅— Me S I-84 5-OSO₂Me i-Pr i-Pr Me S I-85 5-OCH₂CO₂-t-Bu (CH₂)₅—Me S I-86 5-OCH₂CO₂-t-Bu i-Pr i-Pr Me S I-87 5-OCH₂CO₂H —(CH₂)₅— Me SI-88 5-OCH₂CO₂H i-Pr i-Pr Me S I-89 7-OCH₂CO₂-t-Bu —(CH₂)₅— Me S I-907-OCH₂CO₂H —(CH₂)₅— Me S I-91 7-OSO₂Me —(CH₂)₅— Me S I-92 7-OCH₂CN—(CH₂)₅— Me S I-93 7-OBn i-Pr i-Pr Me S I-94 7-OH i-Pr i-Pr Me S I-957-OCH₂CO₂-t-Bu i-Pr i-Pr Me S I-96 7-OCH₂CO₂H i-Pr i-Pr Me S I-977-OSO₂Me i-Pr i-Pr Me S

TABLE 4

No. A R² R³ R⁴ X I-98 I-99

—(CH₂)₅—i-Pr   i-Pr Me Me O O I-100 I-101 I-102 I-103

—(CH₂)₅——(CH₂)₅——(CH₂)₅——(CH₂)₅— —CH₂CH₂OH —CH₂CH₂CH₂OH—CH₂CH₂NMe₂—CH₂CH₂CH₂- NMe₂ S S S S I-104 I-105 I-106 I-107

i-Pr   i-Pr i-Pr   i-Pr n-Pr   n-Pr n-Pr   n-Pr Me Me Me Me S O O SI-108 I-109

—(CH₂)₅——(CH₂)₅— Me Me O S I-110 I-111

—(CH₂)₅——(CH₂)₅— Me Me O S I-112

—(CH₂)₅— Me S

TABLE 5

No. (R¹)_(n) R² R³ R⁴ X I-113 4-Cl i-Pr i-Pr Me S I-114 4-Cl i-Pr i-PrMe O I-115 4-NO₂ —(CH₂)₅— Me S I-116 4-NO₂ —(CH₂)₅— Me O I-117 7-OSO₂Me—(CH₂)₅— Me O I-118 7-OCH₂CO₂-t-Bu —(CH₂)₅— Me O I-119 7-OCH₂CO₂H—(CH₂)₅— Me O I-120 7-OCH₂CN —(CH₂)₅— Me O I-121 4-NO₂ i-Pr i-Pr Me SI-122 4-NO₂ i-Pr i-Pr Me O I-123 4-NHCOMe i-Pr i-Pr Me S I-124 4-NH₂i-Pr i-Pr Me S I-125 4-NHSO₂Me i-Pr i-Pr Me S I-126 4-N(SO₂Me)₂ i-Pri-Pr Me S I-127 4-NHCOPh i-Pr i-Pr Me S I-128 4-NO₂ n-Pr n-Pr Me O I-1294-NO₂ n-Pr n-Pr Me S I-130 4-NH₂ —(CH₂)₅— Me S I-131 4-NH₂ n-Pr n-Pr MeS I-132 4-NHCOMe —(CH₂)₅— Me S I-133 4-OBn —(CH₂)₅— Me S I-134 4-OBni-Pr i-Pr Me S I-135 4-OH —(CH₂)₅— Me S I-136 4-OSO₂Me —(CH₂)₅— Me SI-137 4-OEt —(CH₂)₅— Me S I-138 4-OCH₂CN —(CH₂)₅— Me S I-139 4-OH i-Pri-Pr Me S I-140 4-F —(CH₂)₅— Me S I-141 4-F —(CH₂)₅— Me O I-142 4-F i-Pri-Pr Me S I-143 4-F i-Pr i-Pr Me O I-144 4-CN —(CH₂)₅— Me S I-145 4-CNi-Pr i-Pr Me S I-146 H —(CH₂)₅— —CH₂CH₂OH S I-147 4-F —(CH₂)₅— —CH₂CH₂OHS I-148 4-CN i-Pr i-Pr Me O I-149 H —(CH₂)₅— —CH₂CH₂CH₂OH S I-150 H—(CH₂)₅— —CH₂CH₂NMe₂ S I-151 H —(CH₂)₅— —CH₂CH₂CH₂OH S

TABLE 6 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-1  160-1611.38-1.63(8H, m), 1.73-1.82(2H, m), 2.68(2H, s), 2.70(3H, s), 4.64(2H,s), 7.17(1H, d, J=7.3), 7.39(1H, dd, J=8.2, 4.6), 7.66-7.72(1H, m),7.93(1H, d, J=8.2), 8.46(1H, d, J=8.2), 8.93(1H, dd, J=4.0, 1.7) I-2 111-113 1.59-1.86(8H, m), 2.68(3H, m), 2.77(2H, s), 4.65(2H, s),7.17(1H, d, J=7.6), 7.39(1H, dd, J=8.2, 4.0), 7.69(1H, m), 7.94(1H, d,J=8.6), 8.43(1H, d, J=8.6), 8.94(1H, dd, J=4.0, 2.0) I-3  121-1220.90(6H, t, J=7.3), 1.47-1.64(4H, m), 2.63(2H, s), 2.71(3H, s), 4.56(2H,s), 7.16(1H, d, J=7.6), 7.39(1H, dd, J=8.6, 4.3), 7.69(1H, dd, J=8.6,7.6), 7.93(1H, d, J=8.6), 8.45(1H, d, J=7.6), 8.93(1H, dd, J=4.3, 1.7)I-4  139-140 0.93(6H, t, J=6.9), 1.20-1.58(8H, m), 2.64(2H, s), 2.71(3H,s), 4.56(2H, s), 7.16(1H, d, J=7.6), 7.39(1H, dd, J=8.6, 4.3), 7.69(1H,dd, 8.6, 7.6), 7.93(1H, d, J=8.6), 8.46(1H, d, J=8.6), 8.93(1H, dd,J=4.3, 2.0) I-5  0.83-0.94(6H, m), 1.13-1.35(8H, m), 2.27(3H, s),2.76(2H, s), 3.48(2H, s), 7.46(1H, dd, J=8.6, 4.3), 7.64(1H, dd, J=7.3,1.0), 7.75(1H, dd, J=8.6, 7.6), 8.19(1H, m), 8.42(1H, m), 8.95(1H, dd,J=4.3, 1.0) I-6  106-107 1.31-1.62(8H, m), 1.72-1.85(6H, m), 2.59(2H,s), 2.64(3H, s), 2.66(2H, s), 2.79(2H, s), 4.55(2H, s), 6.72(1H, d,J=7.9), 6.89(1H, d, J=7.9), 7.09(1H, t, J=7.6) I-7  119.5-120.51.34-1.65(10H, m), 1.72-1.85(4H, m), 2.32(3H, s), 2.61(2H, s), 2.65(2H,s), 2.79(2H, s), 3.85(2H, s), 6.63(1H, d, J=7.6), 6.87(1H, d, J=7.6),7.06(1H, t, J=7.6) I-8  101.5-102.5 0.89(6H, t, J=7.6), 1.45-1.68(4H,m), 1.78(4H, m), 2.59(2H, m), 2.61(2H, s), 2.64(3H, s), 2.79(2H, m),4.48(2H, s), 6.71(1H, d, J=7.6), 6.89(1H, d, J=7.6), 7.08(1H, m) I-9 103-104 1.59-1.90(12H, m), 2.58(2H, m), 2.63(3H, s), 2.75(2H, s),2.80(2H, m), 4.56(2H, s), 6.72(1H, d, J=7.6), 6.90(1H, d, J=7.6),7.09(1H, m) I-10 105-106 1.01(6H, d, J=6.9), 1.06(6H, d, J=6.9),1.73-1.84(4H, m), 2.02(2H, sept, J=6.9), 2.59(2H, m), 2.64(3H, s),2.78(2H, s), 2.78(2H, m), 4.66(2H, s), 6.67(1H, d, J=7.6), 6.88(1H, d,J=7.6), 7.07(1H, t, J=7.6) I-11 0.88(6H, t, J=7.6), 1.38-1.60(4H, m),1.73-1.83(4H, m), 2.32(3H, s), 2.59(2H, s), 2.62(2H, m), 2.79(2H, m),3.79(2H, s), 6.63(1H, d, J=7.3), 6.86(1H, d, J=7.3), 7.06(1H, t, d=7.3)I-12 1.76-1.81(4H, m), 2.25(2H, dd, J=13.9, 8.2), 2.39(2H, dd, J=13.9,8.2), 2.59(2H, m), 2.65(3H, s), 2.66(2H, s), 2.80(2H, m), 4.54(2H, s),5.15(2H, s), 5.20(2H, d, J=2.6), 5.76-5.92(2H, m), 6.72(1H, d, J=7.3),6.90(1H, d, J=7.3), 7.09(1H, t, J=7.3) I-13 1.50-1.83(10H, m), 2.30(3H,s), 2.60(2H, m), 2.77(4H, m), 3.88(2H, s), 6.63(1H, d, J=7.6), 6.87(1H,d, J=7.6), 7.06(1H, t, d=7.6) I-14 119-120 0.99(6H, d, J=6.9), 1.01(6H,d, J=6.9), 1.73-1.84(4H, m), 1.96(2H, sept, J=6.9), 2.31(3H, s),2.61(2H, m), 2.72(2H, s), 2.79(2H, m), 3.98(2H, s), 6.60(1H, d, J=7.6),6.86(1H, d, J=7.6), 7.05(1H, t, J=7.6) I-15 1.73-1.85(4H, m),2.14-2.30(4H, m), 2.33(3H, s), 2.62(2H, m), 2.64(2H, s), 2.79(2H, m),3.84(2H, s), 5.15-5.21(4H, m), 5.73-5.89(2H, m), 6.63(1H, d, J=7.6),6.87(1H, d, J=7.6), 7.07(1H, t, J=7.6)

TABLE 7 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-16 127.5-128.50.89(6H, t, J=7.3), 1.45-1.66(4H, m), 2.07(2H, quint, J=7.6), 2.61(2H,s), 2.64(3H, s), 2.88(2H, t, J=7.6), 2.95(2H, t, J=7.6), 4.48(2H, s),6.73(1H, d, J=7.6), 7.03(1H, d, J=7.6), 7.14(1H, t, J=7.6) I-17 110-1111.65-1.88(8H, m), 2.07(2H, quint, J=7.6), 2.63(3H, s), 2.75(2H, s),2.87(2H, t, J=7.6), 2.95(2H, t, J=7.6), 6.74(1H, d, J=7.6), 7.04(1H, d,J=7.6), 7.15(1H, m) I-18 112-114 1.37-1.65(8H, m), 1.76-1.81(2H, m),2.07(2H, quint, J=7.3), 2.64(3H, s), 2.66(2H, s), 2.88(2H, t, J=7.6),2.95(2H, t, J=7.6), 4.56(2H, s), 6.74(1H, d, J=7.6), 7.04(1H, d, J=7.3),7.14(1H, m) I-19 135-136 1.56-1.73(8H, m), 2.06(2H, quint, J=7.3),2.30(3H, s), 2.76(2H, s), 2.87(2H, t, J=7.6), 2.95(2H, t, J=7.6),3.88(2H, s), 6.68(1H, d, J=7.6), 7.02(1H, d, J=7.6), 7.13(1H, m) I-20103-105 1.44-1.57(10H, m), 2.07(2H, quint, J=7.3), 2.32(3H, s), 2.65(2H,s), 2.88(2H, t, J=7.6), 2.95(2H, t, J=7.6), 3.85(2H, s), 6.69(1H, d,J=7.6), 7.02(1H, d, J=7.6), 7.13(1H, m) I-21 1.65-1.90(8H, m), 2.68(3H,s), 2.75(2H, s), 4.65(2H, s), 7.09(1H, d, J=7.2), 7.42-7.52(3H, m),7.68(1H, d, J=7.2), 7.86(1H, m), 8.08(1H, d, J=7.2) I-22   139-140.50.92(6H, t, J=7.3), 1.22-1.55(8H, m), 2.62(2H, s), 2.70(3H, s), 4.57(2H,s), 7.08(1H, d, J=7.3), 7.42-7.51(2H, m), 7.67(1H, d, J=8.2), 7.85(1H,m), 8.06(1H, m) I-23 118-119 1.30-1.85(10H, m), 2.66(2H, s), 2.70(3H,s), 4.65(2H, s), 7.09(1H, d, J=7.3), 7.42-7.53(3H, m), 7.67(1H, d,J=8.2), 7.85(1H, m), 8.07(1H, m) I-24 122.5-123.5 0.89(6H, t, J=7.3),1.45-1.70(4H, m), 2.61(2H, s), 2.70(3H, s), 4.57(2H, s), 7.08(1H, dd,J=7.6, 1.0), 7.42-7.54(3H, m), 7.67(1H, d, J=8.2), 7.86(1H, m), 8.07(1H,m) I-25 108.5-109.5 0.94(6H, t, J=7.3), 1.15-1.49(8H, m), 2.38(3H, s),2.58(2H, s), 3.88(2H, s), 6.98(1H, dd, J=7.3, 1.0), 7.40-7.52(3H, m),7.64(1H, d, J=8.2), 7.85(1H, m), 8.11(1H, m) I-26 125.5-126.51.26-1.70(10H, m), 2.38(3H, s), 2.63(2H, s), 3.93(2H, s), 6.99(1H, dd,J=7.3, 1.3), 7.40-7.52(3H, m), 7.64(1H, d, J=8.2), 7.84(1H, dd, J=4.3,2.3), 8.11(1H, m) I-27 121-122 1.01(6H, d, J=6.9), 1.07(6H, d, J=6.9),2.03(2H, sept, J=6.9), 2.69(3H, s), 2.77(2H, s), 4.75(2H, s), 7.04(1H,dd, J=7.6, 1.0), 7.41-7.53(3H, m), 7.65(1H, d, J=7.9), 7.84(1H, m),8.06(1H, m) I-28 2.26(2H, dd, J=14.2, 8.2), 2.40(2H, dd, J=14.2, 7.3),2.67(2H, s), 2.70(3H, s), 4.64(2H, s), 5.15(2H, m), 5.19(2H, m),5.77-5.89(2H, m), 7.0.9(1H, d, J=7.6), 7.42-7.53(3H, m), 7.68(1H, d,J=7.9), 7.86(1H, m), 8.06(1H, m) I-29 98-99 1.00(6H, d, J=6.9), 1.02(6H,d, J=6.9), 1.97(2H, sept, J=6.9), 2.37(3H, s), 2.69(2H, s), 4.07(2H, s),6.96(1H, dd, J=7.3, 1.0), 7.38-7.52(3H, m), 7.63(1H, d, J=8.6), 7.84(1H,m), 8.11(1H, m) I-30 118-119 1.55-1.94(8H, m), 2.40(3H, s), 2.69(3H, s),2.73(2H, d, J=2.3), 4.57-4.83(2H, m), 7.34(1H, d, J=8.2), 7.40-7.45(2H,m), 7.58(1H, d, J=8.2), 7.80(1H, m), 7.97(1H, m) I-31 134-1351.31-1.84(10H, m), 2.40(3H, s), 2.64(2H, d, J=3.0), 2.71(3H, s),4.51(1H, d, J=12.9), 4.83(1H, d, J=12.9), 7.34(1H, d, J=8.2),7.40-7.47(2H, m), 7.58(1H, d, J=8.2), 7.40-7.47(2H, m), 7.58(1H, d,J=8.2), 7.80(1H, m), 8.00(1H, m)

TABLE 8 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-32 140-1411.57-1.94(8H, m), 2.68(3H, s), 2.76(2H, s), 4.64(2H, s), 7.02(1H, d,J=7.9), 7.51-7.66(3H, m), 8.06(1H, d, J=8.2), 8.27(1H, d, J=7.6) I-33181-182 1.31-1.69(8H, m), 1.73-1.86(2H, m), 2.67(2H, s), 2.70(3H, s),4.64(2H, s), 7.02(1H, d, J=7.9), 7.51-7.66(3H, m), 8.09(1H, d, J=7.6),8.27(1H, d, J=7.9) I-34 1.50-1.83(8H, m), 2.35(3H, s), 2.77(2H, s),3.95(2H, s), 6.92(1H, d, J=7.9), 7.50-7.64(3H, m), 8.07(1H, dd, J=7.6,1.0), 8.26(1H, dd, J=7.6, 1.3) I-35 145.5-146.5 1.37-1.69(10H, m),2.38(3H, s), 2.65(2H, s), 3.93(2H, s), 6.91(1H, d, J=7.9), 7.50-7.65(3H,m), 8.13(1H, d, J=7.6), 8.26(1H, d, J=7.6) I-36 127-128 1.50-1.95(8H,m), 2.68(3H, s), 2.74(2H, s), 3.95(3H, s), 4.69(2H, s), 7.32-7.45(3H,m), 7.68(1H, d, J=8.2), 7.80(1H, d, J=7.6), 7.99(1H, d, J=8.2) I-37137-141 1.32-1.85(10H, m), 2.63(2H, s), 2.70(3H, s), 3.95(3H, s),4.68(2H, s), 7.31-7.48(3H, m), 7.68(1H, d, J=8.9), 7.80(1H, d, J=7.6),8.02(1H, d, J=7.6) I-38 118-119 1.01(6H, d, J=6.9), 1.06(6H, d, J=6.9),2.02(2H, sept, J=6.9), 2.67(3H, s), 2.73(2H, s), 3.94(3H, s), 4.80(2H,s), 7.30-7.45(3H, m), 7.66(1H, d, J=9.2), 7.79(1H, d, J=8.2), 8.01(1H,d, J=8.2) I-39 168-169 1.30-1.71(8H, m), 1.73-1.89(2H, m), 2.66(2H, s),2.69(3H, s), 4.01(3H, s), 4.63(2H, s), 6.79(1H, d, J=8.2), 7.03(1H, d,J=7.6), 7.47-7.55(2H, m), 8.05(1H, m), 8.26(1H, m) I-40 116-118 1.01(6H,d, J=6.9), 1.07(6H, d, J=6.9), 2.03(2H, sept, J=6.9), 2.69(3H, s),2.77(2H, s), 4.01(3H, s), 4.74(2H, s), 6.79(1H, d, J=7.9), 6.98(1H, d,J=7.9), 7.47-7.53(2H, m), 8.05(1H, m), 8.26(1H, m) I-41 187-1881.30-1.69(8H, m), 1.72-1.85(2H, m), 2.67(2H, s), 2.70(3H, s), 4.64(2H,s), 6.97(1H, d, J=7.9), 7.50-7.66(2H, m), 7.75(1H, d, J=7.9), 8.08(1H,d, J=8.2), 8.24(1H, d, J=8.9) I-42 132-133 1.31-1.70(8H, m),1.75-1.90(2H, m), 2.71(5H, s), 4.68(2H, s), 7.19(1H, d, J=7.6), 7.41(1H,d, J=7.6), 7.43-7.57(3H, m), 7.80-7.89(2H, m), 8.16(1H, m), 8.68(1H, d,J=4.0), 8.78(1H, s) I-43 1.01(6H, d, J=6.9), 1.07(6H, d, J=6.9),2.05(2H, sept, J=6.9), 2.68(3H, s), 2.77(2H, s), 2.89(6H, s), 4.74(2H,s), 6.98(1H, d, J=7.9), 7.05(1H, d, J=7.9), 7.42-7.57(2H, m), 8.07(1H,m), 8.24(1H, m) I-44 115-117 1.55-1.94(8H, m), 2.66(3H, s), 2.76(2H, s),2.90(6H, s), 4.63(2H, s), 7.01-7.05(2H, m), 7.44-7.55(2H, m), 8.04(1H,m), 8.25(1H, m) I-45   114-115.5 1.22-1.66(8H, m), 1.75-1.86(2H, m),2.67(2H, s), 2.69(3H, s), 2.90(6H, s), 4.64(2H, s), 7.05(2H, m),7.44-7.55(2H, m), 8.08(1H, m), 8.25(1H, m) I-46 138-139 1.50-1.70(2H,m), 1.80-2.00(2H, m), 2.70(3H, s), 2.73(2H, s), 3.70-3.80(4H, m),4.79(2H, s), 7.09(1H, d, J=7.3), 7.43-7.55(3H, m), 7.69(1H, d, J=8.2),7.87(1H, m), 8.06(1H, m) I-47 96.5-98   1.50-1.70(2H, m), 1.70-1.90(2H,m), 2.38(3H, s), 2.71(2H, s), 3.60-3.80(4H, m), 4.05(2H, s), 6.98(1H,dd, J=7.2, 1.0), 7.40-7.54(3H, m), 7.66(1H, d, J=8.2), 7.85(1H, m),8.10(1H, m)

TABLE 9 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-48 119-1201.60-1.94(8H, m), 2.68(3H, s), 2.75(2H, s), 3.90(3H, s), 4.63(2H, s),7.08(1H, dd, J=7.6, 1.3), 7.17(1H, dd, J=8.9, 2.3), 7.32(1H, m),7.40(1H, d, J=2.4), 7.62(1H, d, J=8.2), 7.76(1H, d, J=8.9) I-49 141-1421.23-1.66(8H, m), 1.72-1.88(2H, m), 2.66(2H, s), 2.69(3H, s), 3.89(3H,s), 4.64(2H, s), 7.07(1H, d, J=7.3), 7.16(1H, dd, J=8.9, 2.6), 7.31(1H,m), 7.46(1H, d, J=2.3), 7.61(1H, d, J=8.2), 7.76(1H, d, J=8.9) I-5093-95 1.02(6H, d, J=6.9), 1.08(6H, d, J=6.9), 2.03(2H, sept, J=6.9),2.70(3H, s), 2.77(2H, s), 3.89(3H, s), 4.74(2H, s), 7.02(1H, dd, J=7.6,1.3), 7.16(1H, dd, J=8.9, 2.6), 7.31(1H, m), 7.44(1H, d, J=2.3),7.59(1H, d, J=8.2), 7.75(1H, d, J=8.9) I-51 116.5-117.5 1.50-1.70(2H,m), 1.90-2.10(2H, m), 2.30-2.60(4H, m), 2.32(3H, s), 2.68(2H, s),2.70(3H, s), 4.70(2H, s), 7.09(1H, d, J=6.3), 7.42-7.55(3H, m), 7.68(1H,d, J=7.9), 7.86(1H, m), 8.06(1H, m) I-52 119-120 1.30-1.70(8H, m),1.39(3H, t, J=7.4), 1.70-1.90(2H, m), 2.65(2H, s), 3.32(2H, q, J=7.4),4.63(2H, s), 7.10(1H, m), 7.42-7.54(3H, m), 7.67(1H, d, J=8.2), 7.85(1H,m), 8.08(1H, m) I-53 95.5-97   1.01(1H, d, J=6.9), 1.06(6H, d, J=6.9),1.37(3H, t, J=7.4), 2.02(2H, sept, J=6.9), 2.76(2H, s), 3.31(2H, q,J=7.4), 4.71(2H, s), 7.05(1H, d, J=6.6), 7.41-7.53(3H, m), 7.65(1H, d,J=8.2), 7.85(1H, m), 8.09(1H, m) I-54 123.5-124.5 1.30-1.70(8H, m),1.70-1.90(2H, m), 2.67(2H, s), 3.47(3H, s), 4.62(2H, s), 5.50(2H, s),7.13(1H, dd, J=7.3, 1.0), 7.43-7.55(3H, m), 7.68(1H, d, J=8.2), 7.86(1H,m), 8.07(1H, m) I-55 106-107 1.01(6H, d, J=6.9), 1.06(6H, d, J=6.9),2.03(2H, sept, J=6.9), 2.79(2H, s), 3.44(3H, s), 4.69(2H, s), 5.48(2H,s), 7.08(1H, d, J=7.3), 7.41-7.53(3H, m), 7.66(1H, d, J=8.2), 7.85(1H,m), 8.08(1H, m) I-56 120-121 1.34(3H, t, J=7.4), 1.30-1.70(10H, m),2.62(2H, s), 2.96(2H, q, J=7.4), 3.92(2H, s), 7.00(1H, dd, J=7.3, 1.0),7.40-7.52(3H, m), 7.64(1H, d, J=8.2), 7.84(1H, m), 8.11(1H, m) I-57101.5-102.5 1.00(6H, d, J=6.9), 1.01(6H, d, J=6.9), 1.32(3H, t, J=7.3),1.97(2H, sept, J=6.9), 2.69(2H, s), 2.94(2H, q, J=7.3), 4.05(2H, s),6.96(1H, dd, J=7.3, 1.0), 7.38-7.52(3H, m), 7.62(1H, d, J=8.2), 7.84(1H,m), 8.12(1H, m) I-58 142-143 1.56-1.94(8H, m), 2.67(3H, s), 2.74(2H, s),3.93(3H, s), 4.64(2H, s), 6.94(1H, dd, J=7.3, 1.0), 7.11-7.15(2H, m),7.41(1H, m), 7.57(1H, d, J=8.2), 7.94(1H, d, J=8.9) I-59 140.5-141.51.24-1.66(8H, m), 1.71-1.85(2H, m), 2.65(2H, s), 2.70(3H, s), 3.93(3H,s), 4.64(2H, s), 6.94(1H, dd, J=7.3, 1.0), 7.11-7.15(2H, m), 7.41(1H,m), 7.56(1H, d, J=7.9), 7.97(1H, d, J=8.9) I-60 141-142 1.01(6H, d,J=6.9), 1.07(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H, s), 2.76(2H,s), 3.93(3H, s), 4.74(2H, s), 6.89(1H, dd, J=7.3, .0), 7.11-7.15(2H, m),7.40(1H, m), 7.54(1H, d, J=8.2), 7.97(1H, d, J=9.6) I-61 121-1221.35-1.86(10H, m), 2.60(2H, s), 2.69(3H, s), 4.61(2H, s), 5.16(2H, s),7.06(1H, d, J=7.6), 7.23-7.47(7H, m), 7.55(1H, d, J=2.3), 7.61(1H, d,J=7.9), 7.78(1H, d, J=8.9) I-62 88-91 1.34-1.85(10H, m), 2.67(2H, s),2.69(3H, s), 4.64(2H, s), 5.07(1H, s), 7.06-7.15(2H, m), 7.26-7.37(2H,m), 7.60(1H, d, J=7.9), 7.77(1H, d, J=8.9)

TABLE 10 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-63 121-1221.60-1.90(8H, m), 2.67(3H, s), 2.74(2H, s), 4.01(3H, s), 4.64(2H, s),6.85(1H, d, J=8.1), 7.10(1H, dd, J=7.3, 1.0), 7.34-7.47(2H, m), 7.60(1H,d, J=8.6), 8.10(1H, d, J=8.2) I-64 150-151 1.30-1.70(8H, m),1.70-1.90(2H, m), 2.65(2H, s), 2.69(3H, s), 4.01(3H, s), 4.64(2H, s),6.85(1H, d, J=7.6), 7.10(1H, dd, J=7.3, 1.0), 7.35-7.47(2H, m), 7.62(1H,d, J=8.2), 8.08(1H, d, J=8.2) I-65 128-129 1.01(6H, d, J=6.9), 1.06(6H,d, J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H, s), 2.76(2H, s), 4.01(3H, s),4.74(2H, s), 6.84(1H, d, J=7.3), 7.05(1H, dd, J=7.3, 1.0), 7.34-7.46(2H,m), 7.63(1H, d, J=8.2), 8.07(1H, d, J=8.6) I-66 142-143 1.50-1.80(8H,m), 2.34(3H, s), 2.75(2H, s), 3.95(2H, s), 4.00(3H, s), 6.84(1H, d,J=7.3), 7.00(1H, dd, J=7.3, 1.0), 7.34-7.45(2H, m), 7.62(1H, d, J=8.6),8.06(1H, d, J=8.2) I-67 125-126 1.30-1.70(10H, m), 2.37(3H, s), 3.92(2H,s), 4.00(3H, s), 6.85(1H, d, J=7.6), 7.00(1H, dd, J=7.3, 1.0),7.35-7.45(2H, m), 7.67(1H, d, J=8.6), 8.06(1H, d, J=8.6) I-68 152-1530.99(6H, d, J=6.9), 1.01(6H, d, J=6.9), 1.97(2H, sept, J=6.9), 2.36(3H,s), 2.68(2H, s), 4.00(3H, s), 4.06(2H, s), 6.84(1H, d, J=6.9), 6.97(1H,dd, J=7.3, 1.0), 7.35-7.44(2H, m), 7.67(1H, d, J=8.6), 8.05(1H, d,J=8.2) I-69 146-148 1.30-1.84(10H, m), 2.65(2H, s), 2.69(3H, s),4.64(2H, s), 5.19(2H, s), 6.94(1H, d, J=7.3, 1.6), 7.19-7.23(2H, m),7.31-7.55(7H, m), 7.98(1H, d, J=8.6) I-70 144-145 1.01(6H, d, J=6.9),1.07(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H, s), 2.76(2H, s),4.74(2H, s), 5.19(2H, s), 6.89(1H, dd, J=7.3, 1.0), 7.19-7.23(2H, m),7.31-7.54(7H, m), 7.99(1H, d, J=8.6) I-71 167-168 1.31-1.85(10H, m),2.66(2H, s), 2.69(3H, s), 4.64(2H, s), 5.08(1H, s), 6.93(1H, dd, J=7.3,1.3), 7.08(1H, dd, J=8.9, 2.6), 7.16(1H, d, J=2.6), 7.40(1H, m),7.50(1H, d, J=8.2), 7.99(1H, d, J=8.9) I-72 1.31-1.85(10H, m), 2.67(2H,s), 2.70(3H, s), 3.20(3H, s), 4.64(2H, s), 7.12(1H, dd, J=7.3, 1.0),7.39(1H, dd, J=9.2, 2.3), 7.52(1H, m), 7.66(1H, d, J=8.2), 7.76(1H, d,J=2.6), 8.18(1H, d, J=9.2) I-73 1.30-1.84(10H, m), 1.50(9H, s), 2.66(2H,s), 2.69(3H, s), 4.63(2H, s), 4.64(2H, s), 6.96(1H, dd, J=7.3, 1.0),7.07(1H, d, J=2.6), 7.21(1H, dd, J=9.2, 2.6), 7.4(1H, m), 7.52(1H, d,J=8.2), 8.00(1H, d, J=9.2) I-74 139-142(dec.) 1.30-1.86(10H, m),2.36(1H, s), 2.66(2H, s), 2.69(3H, s), 4.64(2H, s), 4.80(2H, s),6.98(1H, dd, J=7.3, 1.0), 7.12-7.28(2H, m), 7.43(1H, m), 7.55(1H, d,J=8.2), 8.03(1H, d, J=9.2) I-75 119-120 1.01(6H, d, J=6.9), 1.07(6H, d,J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H, s), 2.77(2, s), 4.74(2H, s),5.10(1H, brs), 6.88(1H, d, J=7.3), 7.07(1H, dd, J=8.9, 2.3), 7.15(1H, d,J=2.6), 7.38(1H, m), 7.48(1H, d, J=8.2), 7.99(1H, dd, J=8.9) I-761.02(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.70(3H,s), 2.78(2H, s), 3.19(3H, s), 4.74(2H, s), 7.07(1H, dd, J=7.3, 1.0),7.39(1H, dd, J=9.2, 2.6), 7.51(1H, m), 7.64(1H, d, J=8.2), 7.75(1H, d,J=3.3), 8.18(1H, d, J=9.2)

TABLE 11 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-77 1.01(6H, d,J=6.9), 1.07(6H, d, J=6.9), 1.50(9H, s), 2.02(2H, sept, J=6.9), 2.69(3H,s), 2.76(2H, s), 4.63(2H, s), 4.74(2H, s), 6.91(1H, m), 7.07(1H, d,J=2.6), 7.20(1H, dd, J=9.2, 2.6), 7.40(1H, m), 7.51(1H, d, J=8.6),7.99(1H, d, J=9.2) I-78 150-152(dec.) 1.01(6H, d, J=6.9), 1.06(6H, d,J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H, s), 2.77(2H, s), 4.74(2H, s),4.80(2H, s), 6.94(1H, d, J=6.6), 7.13(1H, d, J=2.6), 7.21(1H, dd, J=9.2,2.6), 7.42(1H, m), 7.54(1H, d, J=7.9), 8.03(1H, d, J=8.9) I-79 154-1551.30-1.70(8H, m), 1.70-1.90(2H, m), 2.65(2H, s), 2.69(3H, s), 4.64(2H,s), 5.26(2H, s), 6.93(1H, d, J=7.3), 7.11(1H, dd, J=7.3, 1.0),7.32-7.48(5H, m), 7.52-7.56(2H, m), 7.65(1H, d, J=8.6), 8.18(1H, d,J=8.2) I-80 129-130 1.01(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.02(2H,sept, J=6.9), 2.69(3H, s), 2.76(2H, s), 4.75(2H, s), 5.26(2H, s),6.92(1H, d, J=7.3), 7.06(1H, dd, J=7.3, 1.0), 7.33-7.47(5H, m),7.52-7.56(2H, m), 7.65(1H, d, J=8.6), 8.17(1H, d, J=8.2) I-81 69.5-71  1.30-1.70(8H, m), 1.70-1.90(2H, m), 2.66(2H, s), 2.69(3H, s), 4.64(2H,s), 5.54(1H, s), 6.85(1H, m), 7.10(1H, m), 7.30(1H, m), 7.46(1H, dd,J=8.2, 7.3), 7.63(1H, d, J=8.6), 8.01(1H, d, J=8.2) I-82 110-1121.01(6H, d, J=6.9), 1.06(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.69(3H,s), 2.76(2H, s), 4.74(2H, s), 5.43(1H, brs), 6.84(1H, d, J=6.6),7.05(1H, d, J=6.6), 7.29(1H, m), 7.45(1H, m), 7.64(1H, d, J=8.2),7.99(1H, d, J=8.6) I-83 166.5-167.5 1.30-1.70(8H, m), 1.70-1.90(2H, m),2.68(2H, s), 2.70(3H, s), 3.22(3H, s), 4.65(2H, s), 7.18(1H, d, J=6.6),7.47(1H, m), 7.53-7.60(2H, m), 7.95(1H, d, J=8.2), 8.06(1H, d, J=8.2)I-84 128.5-129.5 1.02(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.02(2H, sept,J=6.9), 2.69(3H, s), 2.79(2H, s), 3.21(3H, s), 4.74(2H, s), 7.12(1H, d,J=7.3), 7.46(1H, t, J=7.9), 7.52-7.59(2H, m), 7.93(1H, d, J=8.6),8.06(1H, d, J=8.6) I-85 129-130 1.31-1.70(8H, m), 1.70-1.90(2H, m),1.51(9H, s), 2.65(2H, s), 2.69(3H, s), 4.64(2H, s), 4.71(2H, s),6.74(1H, d, J=7.6), 7.11(1H, d, J=6.6), 7.34(1H, t, J=8.1), 7.46(1H, dd,J=8.4, 7.4), 7.67(1H, d, J=8.2), 8.20(1H, d, J=8.2) I-86 112-1131.01(6H, d, J=6.9), 1.07(6H, d, J=6.9), 1.51(9H, s), 2.02(2H, sept,J=6.9), 2.69(3H, s), 2.76(2H, s), 4.70(2H, s), 4.74(2H, s), 6.73(1H, d,J=7.3), 7.06(1H, d, J=6.3), 7.34(1H, t, J=8.1), 7.45(1H, m), 7.67(1H, d,J=8.2), 8.18(1H, d, J=8.2) I-87 153-154.5(dec.) 1.30-1.70(8H, m),1.70-1.90(2H, m), 2.65(2H, s), 2.69(3H, s), 4.64(2H, s), 4.86(2H, s),6.78(1H, d, J=7.6), 7.13(1H, d, J=7.3), 7.36(1H, m), 7.48(1H, m),7.71(1H, d, J=8.6), 8.15(1H, d, J=8.2) I-88 156.5-158(dec.) 1.01(6H, d,J=6.9), 1.06(6H, d, J=6.9), 2.01(2H, sept, J=6.9), 2.69(3H, s), 2.76(2H,s), 4.74(2H, s), 4.86(2H, s), 6.78(1H, d, J=7.6), 7.08(1H, d, J=6.6),7.36(1H, m), 7.47(1H, m), 7.72(1H, d, J=8.6), 8.13(1H, d, J=8.2)

TABLE 12 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-89 131-1321.31-1.88(10H, m), 1.57(9H, s), 2.65(2H, s), 2.74(3H, s), 4.60(2H, s),4.65(2H, s), 7.07(1H, d, J=6.3), 7.27(1H, m), 7.34(1H, d, J=7.6),7.47(1H, d, J=2.6), 7.61(1H, d, J=8.2), 7.78(1H, d, J=9.2) I-90124-130(dec.) 1.31-1.90(10H, m), 2.65(2H, s), 2.73(3H, s), 4.64(2H, s),4.77(2H, s), 7.09(1H, d, J=7.3), 7.26(1H, m), 7.36(1H, m), 7.51(1H, d,J=2.3), 7.63(1H, d, J=8.2), 7.81(1H, d, J=8.9) I-91 130-1311.31-1.87(10H, m), 2.67(2H, s), 2.71(3H, s), 3.16(3H, s), 4.65(2H, s),7.16(1H, d, J=7.3), 7.40-7.53(2H, m), 7.69(1H, d, J=7.9), 7.91(1H, d,J=8.9), 8.10(1H, s) I-92 155-156 1.31-1.87(10H, m), 2.68(2H, s),2.73(3H, s), 4.66(2H, s), 4.87(2H, s), 7.11(1H, d, J=7.3), 7.19(1H, dd,J=8.9, 2.3), 7.40(1H, m), 7.55(1H, d, J=2.3), 7.64(1H, d, J=7.9),7.82(1H, d, J=9.2) I-93 1.02(6H, d, J=6.9), 1.08(6H, d, J=6.9),1.96-2.10(2H, m), 2.68(3H, s), 2.74(2H, s), 4.73(2H, s), 5.14(2H, s),7.02(1H, d, J=7.3), 7.22-7.61(9H, m), 7.77(1H, d, J=8.9) I-94 1.01(6H,d, J=6.9), 1.07(6H, d, J=6.9), 2.03(2H, sept, J=6.9), 2.69(3H, s),2.78(2H, s), 4.74(2H, s), 5.17(1H, brs), 7.02(1H, d, J=7.3), 7.13(1H,dd, J=8.9, 2.6), 7.29(1H, m), 7.37(1H, d, J=2.3), 7.58(1H, d, J=8.2),7.76(1H, d, J=8.9) I-95 1.02(6H, d, J=6.9), 1.09(6H, d, J=6.9), 1.48(9H,s), 2.04(2H, sept, J=6.9), 2.73(3H, s), 2.76(2H, s), 4.59(2H, s),4.75(2H, s), 7.02(1H, d, J=7.3), 7.23-7.34(2H, m), 7.45(1H, d, J=2.6),7.59(1H, d, J=8.6), 7.77(1H, d, J=8.9) I-96 148-150 1.02(6H, d, J=6.9),1.08(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.72(3H, s), 2.76(2H, s),4.73(2H, s), 4.76(2H, s), 7.04(1H, d, J=7.3), 7.25(1H, m), 7.34(1H, m),7.50(1H, d, J=2.6), 7.61(1H, d, J=7.9), 7.80(1H, d, J=8.9) I-97  98-1001.02(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.02(2H, sept, J=6.9), 2.71(3H,s), 2.79(2H, s), 3.15(3H, s), 4.74(2H, s), 7.11(1H, d, J=7.6),7.39-7.51(2H, m), 7.67(1H, d, J=8.2), 7.90(1H, d, J=8.2), 8.09(1H, d,J=2.6) I-98 156-157 1.36-1.68(10H, m), 2.35(3H, s), 2.69(2H, s),3.95(2H, s), 7.08(1H, dd, J=7.3, 0.7), 7.57(1H, dd, J=8.9, 7.3),7.81(1H, dd, J=8.9, 0.7) I-99 110-111 1.00(6H, d, J=6.9), 1.03(6H, d,J=6.9), 1.98(2H, sept., J=6.9), 2.34(3H, s), 2.75(2H, s), 4.07(2H, s),7.05(1H, dd, J=7.3, 1.0), 7.56(1H, dd, J=8.9, 7.3), 7.75(1H, dd, J=8.9,1.0)  I-100 102.5-104   1.22-1.66(8H, m), 1.68-1.85(6H, m),1.94-2.08(1H, m), 2.50-2.68(2H, m), 2.66(2H, s), 2.71-2.84(2H, m),3.56(2H, t, J=5.9), 3.85-4.00(2H, m), 4.52(2H, s), 6.73(1H, d, J=7.6),6.90(1H, d, J=7.6), 7.09(1H, t, J=7.6)  I-101   87-88.5 1.25-1.64(8H,m), 1.69-1.86(7H, m), 1.93-2.04(2H, m), 2.51-2.68(2H, m), 2.65(2H, s),2.72-2.87(2H, m), 3.40-3.46(2H, m), 3.71-3.78(2H, m), 4.53(2H, s),6.72(1H, d, J=7.6), 6.90(1H, d, J=7.6), 7.09(1H, t, J=7.6)  I-10294.5-95.5 1.31-1.66(8H, m), 1.70-1.85(6H, m), 2.31(6H, s), 2.54-2.69(4H,m), 2.64(2H, s), 2.74-2.83(2H, m), 3.42(2H, t, J=7.6), 4.52(2H, s),6.73(1H, d, J=7.6), 6.89(1H, d, J=7.6), 7.08(1H, t, J=7.6)

TABLE 13 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-1031.28-1.95(16H, m), 2.23(6H, s), 2.35-2.41(2H, m), 2.51-2.66(2H, m),2.64(2H, s), 2.71-2.84(2H, m), 3.25-3.32(2H, m), 4.53(2H, s), 6.72(1H,d, J=7.6), 6.89(1H, d, J=7.6), 7.09(1H, t, J=7.6) I-104 1.01(6H, d,J=6.9), 1.07(6H, d, J=6.9), 1.97-2.12(4H, m), 2.64(3H, s), 2.78(2H, s),2.87(2H, t, J=7.6), 2.95(2H, t, J=7.6), 4.66(2H, s), 6.70(1H, d, J=7.6),7.02(1H, d, J=7.6), 7.13(1H, t, J=7.6) I-105 118-119 0.99(6H, d, J=7.3),1.01(6H, d, J=7.3), 1.85-2.12(4H, m), 2.31(3H, s), 2.73(2H, s), 2.86(2H,t, J=7.6), 2.94(2H, t, J=7.6), 3.97(2H, s), 6.66(1H, d, J=7.6), 7.00(1H,d, J=7.6), 7.12(1H, d, t=7.6) I-106 105-106 0.93(6H, t, J=6.9),1.10-1.60(8H, m), 2.07(2H, quint, J=7.6), 2.32(3H, s), 2.60(2H, s),2.88(2H, t, J=7.6), 2.95(2H, t, J=7.6), 3.79(2H, s), 6.67(1H, d, J=7.6),7.01(1H, d, J=7.6), 7.12(1H, t, J=7.6) I-107 144-145 0.92(6H, t, J=6.9),1.10-1.60(8H, m), 2.07(2H, quint, J=7.6), 2.62(2H, s), 2.64(3H, s),2.88(2H, t, J=7.6), 2.95(2H, t, J=7.6), 4.48(2H, s), 6.73(1H, d, J=7.6),7.04(1H, d, J=7.6), 7.14(1H, t, J=7.6) I-108 165-168 1.30-1.71(10H, m),2.30(3H, s), 2.66(2H, s), 3.86(2H, s), 4.27(2H, s), 4.27(2H, s),6.52(1H, d, J=7.8), 6.67(1H, d, J=8.1), 6.80(1H, dd, J=8.1, 7.8) I-109148-150 1.30-1.65(8H, m), 1.70-1.85(2H, m) 2.63(3H, s), 2.67(2H, s),4.28(2H, s), 4.28(2H, s), 4.58(2H, s), 6.60(1H, d, J=7.8), 6.70(1H, d,J=8.1), 6.82(1H, dd, J=8.1, 7.8) I-110 1.30-1.74(10H, m), 2.31(3H, s),2.69(2H, s), 3.86(2H, s), 5.98(2H, s), 6.54(1H, d, J=7.8), 6.65(1H, d,J=7.8), 6.81(1H, t, J=7.8) I-111 124-126 1.21-1.70(8H, m), 1.73-1.84(2H,m) 2.63(3H, s), 2.69(2H, s), 4.58(2H, s), 5.99(2H, s), 6.61(1H, d,J=8.1), 6.67(1H, d, J=7.8), 6.83(1H, dd, J=8.1, 7.8) I-112 142-1441.21-1.85(10H, m), 1.97(2H, m), 2.61(2H, m), 2.64(3H, s), 2.65(2H, s),2.91(3H, s), 3.21(2H, t, J=5.9), 4.54(2H, s), 6.27(1H, d, J=7.9),6.43(1H, d, J=7.9), 7.05(12H, t, J=7.9) I-113 86.5-87.5 1.01(6H, d,J=6.9), 1.06(6H, d, J=6.9), 2.08(2H, sept, J=6.9), 2.69(3H, s), 2.78(2H,s), 4.73(2H, s), 6.97(1H, d, J=7.9), 7.50-7.65(3H, m), 8.09(1H, d,J=7.9), 8.26(1H, d, J=7.9) I-114 111.5-112.5 1.00(6H, d, J=6.9),1.01(6H, d, J=6.9), 1.97(2H, sept, J=6.9), 2.37(3H, s), 2.71(2H, s),4.06(2H, s), 6.88(1H, d, J=7.9), 7.49-7.65(3H, m), 8.12(1H, m), 8.26(1H,m) I-115   178-179.5 1.39-1.79(10H, m), 2.70(3H, s), 2.71(2H, s),4.66(2H, s), 7.12(1H, d, J=7.9), 7.60(1H, m), 7.75(1H, m), 8.15(1H, m),8.34(1H, d, J=7.9), 8.74(1H, d, J=7.9) I-116 135-136 1.47-1.59(10H, m),2.38(3H, s), 2.69(2H, s), 3.95(2H, s), 7.02(1H, d, J=8.6), 7.60(1H, m),7.75(1H, m), 8.19(1H, d, J=8.6), 8.33(1H, d, J=8.6), 8.75(1H, d, J=8.6)

TABLE 14 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-117 127.5-128.51.36-1.69(10H, m), 2.38(3H, s), 2.65(2H, s), 3.16(3H, s), 3.93(2H, s),7.04-7.08(1H, m), 7.40-7.51(2H, m), 7.66(1H, d, J=8.2), 7.90(1H, d,J=8.9), 8.11(1H, d, J=2.3) I-118 130.5-131.5 1.37-1.70(10H, m), 1.48(9H,s), 2.42(3H, s), 2.61(2H, s), 3.93(2H, s), 4.63(2H, s), 6.94-6.98(1H,m), 7.22-7.33(2H, m), 7.55(1H, d, J=2.6), 7.59(1H, d, J=8.2), 7.77(1H,d, J=8.9) I-119 155.5-156.5 1.32-1.68(10H, m), 2.39(3H, s), 2.60(2H, s),3.92(2H, s), 4.77(2H, s), 6.96-7.00(1H, m), 7.22-7.36(2H, m),7.55-7.61(1H, m), 7.77(1H, d, J=8.9) I-120 127-128 1.35-1.69(10H, m),2.42(3H, s), 2.65(2H, s), 3.94(2H, s), 4.89(2H, s), 6.99-7.03(1H, m),7.19(1H, dd, J=8.9, 2.6), 7.34-7.40(1H, m), 7.59-7.65(2H, m), 7.81(1H,d, J=8.9) I-121 131-132 1.02(6H, d, J=6.9), 1.06(6H, d, J=6.9), 2.01(2H,sept, J=6.9), 2.69(3H, s), 2.82(2H, s), 4.73(2H, s), 7.06(1H, d, J=8.2),7.60(1H, m), 7.75(1H, m), 8.16(1H, d, J=7.9), 8.34(1H, d, J=8.2),8.75(1H, d, J=8.2) I-122 150-151 1.01(6H, d, J=6.9), 1.02(6H, d, J=6.9),1.99(2H, sept, J=6.9), 2.37(3H, s), 2.75(2H, s), 4.08(2H, s), 6.99(1H,d, J=8.2), 7.60(1H, m), 7.74(1H, m), 8.19(1H, d, J=8.2), 8.33(1H, d,J=8.2), 8.75(1H, d, J=8.6) I-123 173-175 1.01(6H, d, J=6.9), 1.07(6H, d,J=6.9), 2.02(2H, sept, J=6.9), 2.32(3H, s), 2.69(3H, s), 2.78(2H, s),4.73(2H, s), 7.05(1H, d, J=7.9), 7.20-7.58(3H, m), 7.84(1H, m), 8.11(1H,d, J=7.9) I-124 1.01(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.04(2H, sept,J=6.9), 2.68(3H, s), 2.77(2H, s), 4.09(2H, brs), 4.73(2H, s), 6.76(1H,d, J=7.9), 6.94(1H, d, J=7.9), 7.44-7.52(2H, m), 7.83(1H, m), 8.10(1H,m) I-125 183-184 1.02(6H, d, J=6.9), 1.09(6H, d, J=6.9), 2.02(2H, sept,J=6.9), 2.69(3H, s), 2.79(2H, s), 3.00(3H, s), 4.74(2H, s), 6.70(1H, s),7.06(1H, d, J=7.9), 7.52-7.65(3H, m), 8.06(1H, d, J=7.9), 8.14(1H, d,J=7.9) I-126 225-226 1.01(6H, d, J=6.9), 1.06(6H, d, J=6.9), 2.01(2H,sept, J=6.9), 2.68(3H, s), 2.79(2H, s), 3.51(6H, s), 4.74(2H, s),7.07(1H, d, J=7.9), 7.48-7.68(3H, m), 8.05(1H, d, J=7.9), 8.11(1H, d,J=7.9) I-127 153-154 1.02(6H, d, J=6.9), 1.07(6H, d, J=6.9), 2.03(2H,sept, J=6.9), 2.70(3H, s), 2.79(2H, s), 4.75(2H, s), 7.11(1H, d, J=8.2),7.49-7.61(5H, m), 7.89-8.17(5H, m) I-128 140-141 0.95(6H, t, J=6.9),1.21-1.53(8H, m), 2.39(3H, s), 2.64(2H, s), 3.89(2H, s), 7.01(1H, d,J=8.2), 7.60(1H, m), 7.75(1H, m), 8.19(1H, d, J=8.2), 8.33(1H, d,J=8.2), 8.75(1H, d, J=8.2) I-129 171.5-172.5 0.92(6H, t, J=6.9),1.26-1.61(8H, m), 2.67(2H, s), 2.7.0(3H, s), 4.57(2H, s), 7.10(1H, d,J=8.2), 7.60(1H, m), J=7.76(1H, m), 8.15(1H, d, J=7.9), 8.34(1H, d,J=8.2), 8.74(1H, d, J=8.2)

TABLE 15 Comp. Physical Data No. m.p. ° C. NMR (CDCl₃) I-130 135-1361.42-1.82(10H, m), 2.66(2H, s), 2.68(3H, s), 4.11(2H, brs), 4.62(2H, s),6.77(1H, d, J=7.9), 7.00(1H, d, J=7.9), 7.45-7.53(2H, m), 7.83(1H, m),8.12(1H, m) I-131   133-134.5 0.92(6H, t, J=6.9), 1.18-1.59(8H, m),2.62(2H, s), 2.69(3H, s), 4.10(2H, brs), 4.54(2H, s), 6.77(1H, d,J=7.9), 6.99(1H, d, J=7.9), 7.44-7.52(2H, m), 7.83(1H, m), 8.11(1H, m)I-132 219-220 1.30-1.78(10H, m), 2.18(3H, s), 2.64(3H, s), 2.78(2H, s),4.60(2H, s), 7.08(1H, d, J=8.2), 7.53-7.65(3H, m), 8.02-8.09(2H, m),9.90(1H, s) I-133 139-140 1.25-1.88(10H, m), 2.67(2H, s), 2.69(3H, s),4.64(2H, s), 5.26(2H, s), 6.88(1H, d, J=7.9), 7.03(1H, d, J=7.9),7.36-7.56(7H, m), 8.06(1H, m), 8.36(1H, m) I-134 104.5-105.5 1.01(6H, d,J=6.9), 1.07(6H, d, J=6.9), 2.03(2H, sept, J=6.9), 2.69(3H, s), 2.77(2H,s), 4.74(2H, s), 5.25(2H, s), 6.87(1H, d, J=8.3), 6.97(1H, d, J=8.3),7.33-7.55(7H, m), 8.06(1H, m), 8.34(1H, m) I-135 142-143 1.28-1.68(8H,m), 1.71-1.87(2H, m), 2.66(2H, s), 2.69(3H, s), 4.29(2H, s), 5.28(1H,s), 6.81(1H, d, J=7.9), 6.97(1H, d, J=7.9), 7.48-7.55(2H, m), 8.07(1H,m), 8.18(1H, m) I-136 166-167 1.30-1.67(8H, m), 1.72-1.89(2H, m),2.69(5H, s), 3.21(3H, s), 4.64(2H, s), 7.08(1H, d, J=8.2), 7.50-7.63(3H,m), 8.08-8.14(2H, m) I-137 173-174 1.20-1.68(11H, m), 1.72-1.89(2H, m),2.66(2H, s), 2.69(3H, s), 4.21(2H, q, J=7.3), 4.63(2H, s), 6.78(1H, d,J=8.2), 7.02(1H, d, J=8.2), 7.45-7.53(2H, m), 8.04(1H, m), 8.31(1H, m)I-138 1.29-1.68(8H, m), 1.73-1.87(2H, m), 2.67(2H, s), 2.70(3H, s),4.64(2H, s), 4.97(2H, s), 6.92(1H, d, J=7.9), 7.04(1H, d, J=7.9),7.50-7.60(2H, m), 8.07(1H, m), 8.21(1H, m) I-139 1.01(6H, d, J=6.9),1.07(6H, d, J=6.9), 2.03(2H, sept, J=6.9), 2.69(3H, s), 2.77(2H, s),4.73(2H, s), 5.26(1H, s), 6.80(1H, d, J=7.9), 6.91(1H, d, J=6.9),7.47-7.56(2H, m), 8.05(1H, m), 8.18(1H, m) I-140 139-140 1.25-1.87(10H,m), 2.67(2H, s), 2.70(3H, s), 4.64(2H, s), 7.02(1H, m), 7.13(1H, m),7.55(2H, m), 8.09(2H, m) I-141 111-112 1.31-1.75(10H, m), 2.38(3H, s),2.64(2H, s), 3.92(2H, s), 6.89(1H, m), 7.10(1H, m), 7.55(2H, m),8.10(2H, m) I-142 118-119 1.01(6H, d, J=6.9), 1.07(6H, d, J=6.9),2.02(2H, sept, J=6.9), 2.69(3H, s), 2.77(2H, s), 4.73(2H, s), 6.96(1H,dd, J=7.3, 4.9), 7.11(1H, dd, J=10.6, 8.2), 7.55(2H, m), 8.08(2H, m)I-143 109-110 1.00(6H, d, J=6.9), 1.02(6H, d, J=6.9), 1.97(2H, sept,J=6.9), 2.37(3H, s), 2.70(2H, s), 4.06(2H, s), 6.88(1H, dd, J=7.6, 4.6),7.09(1H, dd, J=10.2, 7.9), 7.55(2H, m), 8.07(2H, m)

TABLE 16 Comp. Physical Data No. m.p. ° C. NMR(CDCl₃) I-144 164-1651.31-1.88(10H, m), 2.69(5H, s), 4.56(2H, s), 7.11(1H, d, J=7.9),7.60(1H, m), 7.72(1H, m), 7.90(1H, d, J=7.9), 8.13(1H, d, J=8.2),8.25(1H, d, J=7.9 I-145   137-138.5 1.01(6H, d, J=6.9), 1.06(6H, d,J=6.9), 2.01(2H, sept, J=6.9), 2.69(3H, s), 2.80(2H, s), 4.73(2H, s),7.06(1H, d, J=7.9), 7.59(1H, m), 7.71(1H, m), 7.87(1H, d, J=7.6),8.13(1H, d, J=8.2), 8.24(1H, d, J=8.6) I-146 131.5-133   1.28-1.62(8H,m), 1.70-1.85(2H, m), 1.99(1H, t, J=6.3), 2.67(2H, s), 3.61(2H, t,J=5.9), 3.97(2H, dt, J=6.3, 5.9), 4.62(2H, s), 7.11(1H, d, J=7.6),7.42-7.54(3H, m), 7.68(1H, d, J=8.2), 7.83-7.88(1H, m), 8.02-8.06(1H, m)I-147 90-92 1.24-1.65(8H, m), 1.71-1.86(2H, m), 1.99(1H, t, J=5.9),2.68(2H, s), 3.61(2H, t, J=5.9), 3.97(2H, q, J=5.9), 4.61(2H, s),7.01-7.17(2H, m), 7.50-7.61(2H, m), 8.03-8.12(2H, m) I-148 153-1541.01(6H, d, J=6.9), 1.02(6H, d, J=6.9), 1.98(2H, sept, J=6.9), 2.37(3H,s), 2.73(2H, s), 4.07(2H, s), 6.99(1H, d, J=7.9), 7.59(1H, m), 7.70(1H,m), 7.86(1H, d, J=7.9), 8.16(1H, d, J=8.2), 8.23(1H, d, J=8.2) I-149124.5-125.5 1.25-1.87(11H, m), 1.97-2.08(2H, m), 2.66(2H, s),3.45-3.52(2H, m), 3.74-3.82(2H, m), 4.63(2H, s), 7.10(1H, d, J=7.3),7.42-7.54(3H, m), 7.67(1H, d, J=8.6), 7.83-7.88(1H, m), 8.05-8.09(1H, m)I-150 111.5-113   1.30-1.67(8H, m), 1.71-1.86(2H, m), 2.33(6H, s),2.65(2H, s), 2.69(2H, t, J=7.6), 3.48(2H, t, J=7.6), 4.62(2H, s),7.10(1H, d, J=7.3), 7.42-7.54(3H, m), 7.67(1H, d, J=8.2), 7.83-7.87(1H,m), 8.08-8.12(1H, m) I-151 105-106 1.31-1.65(8H, m), 1.73-1.86(2H, m),1.94(2H, quint., J=7.6), 2.24(6H, s), 2.41(2H, t, J=7.6), 2.65(2H, s),3.35(2H, t, J=7.6), 4.62(2H, s), 7.09(1H, d, J=7.3), 7.42-7.53(3H, m),7.67(1H, d, J=8.2), 7.83-7.87(1H, m), 8.08-8.11(1H, m)

The above compounds of the present invention were examined as shownbelow.

Example 1 Experiments for Human CB receptor (CBR) Binding Inhibition

The crude membrane fractions were then prepared from the CB1R orCB2R-expressing CHO cells. Receptor binding assay was performed byincubating the membranes with each test compound and 38,000 dpm[³H]CP55940 (at a final concentration of 0.5 nM: PerkinElmer Life &Analytical Sciences) in the assay buffer (50 mM Tris-HCl, 1 mM EDTA, 3mM MgCl₂, pH 7.4) containing 0.5% bovine serum albumin (BSA) for 2 hr at25° C. The incubation mixture was filtered through 1% polyethylenimine(PEI)-treated GF/C glass filter and washed with 50 mM Tris-HCl (pH 7.4)containing 0.1% BSA. The radioactivity was then counted with a liquidscintillation counter. Nonspecific binding was determined in thepresence of 10 μM WIN55212-2 (a CBR agonist described in the patent U.S.Pat. No. 508,122, Sigma), and the specific binding was calculated bysubtracting the nonspecific binding from the total binding. The IC₅₀value for each test compound was determined as the concentration atwhich 50 % of the specific binding was inhibited. As a consequence ofthese studies, the Ki values of each test compound were determined fromthe IC₅₀ value and the Kd vale of [³H]CP55940. TABLE 17 CB receptorbinding inhibition Ki Compound (nM) No. CB1 CB2 I-6 15.0 0.2 I-14 16.01.6 I-22 20.0 1.5 I-23 29.6 6.0 I-25 42.5 1.0 I-27 13.0 0.3 I-28 31.44.8 I-29 6.0 1.7 I-33 20.7 1.2 I-43 21.4 11.3 I-77 35.0 1.5 I-105 23 2.2I-108 21 0.7 I-109 30 1 I-113 10 0.9 I-114 25 5.9 I-140 59 0.8 I-142 201.2 I-143 29 1.4 I-144 54 1

Example 2 Inhibition Experiments for CBR-mediated Suppression of cAMPSynthesis

The CHO cells expressing human CB1R or CB2R were incubated with testcompounds for 15 min. After the incubation, 4 μM forskolin (Sigma) wasadded and the cells were incubated for 20 min. The reaction was stoppedby the addition of 1N HCl and the amount of cAMP in the cell supernatantwas measured using an Cyclic AMP kit (CIS bio international) accordingto the manufacture's protocol. The cAMP amount increased by forskolincompared to that in the absence of forskolin was defined as 100%, andthe IC₅₀ value of each test compound was determined as the concentrationat which 50% of the forskolin-stimulated cAMP synthesis was inhibited.TABLE 18 Inhibition of cAMP synthesis Compound IC₅₀ (nM) No. CB1 CB2 I-63.2 0.2 I-10 n.t. 0.2 I-14 4 2.7 I-23 10.4 1.7 I-27 8.1 n.t. I-29 17.5n.t. I-105 25 n.t. I-113 13 1.5 I-114 24 48 I-140 27 n.t. I-142 14 n.t.I-143 35 n.t. I-144 52 n.t.n.t.: not tested

Example 3 Inhibitory Effect against Formalin-induced Hyperalgesia in ICRMice

The inhibitory effects of the compounds of the present invention againstformalin-induced hyperalgesia were examined in male ICR mice (5W). Testcompounds were dissolved in sesami oil and applied orally 2 h prior tothe subcutaneous formalin injection (2% 20 μL) into the right hind paw.In this experiment, observation period was set to 30 min and dividedinto two parts, the first 5 minutes immediately after the formalininjection (first phase) and 10 to 30 min minutes after the formalininjection (second phase). The strength for pain sensation was evaluatedby the total time for licking and biting behavior. The inhibitory effectof the test compounds on such behavior was evaluated and the ED₅₀ valuewas calculated. TABLE 19 Oral administration Inhibitory effect againstformalin-induced hyperalgesia (ED₅₀) Compound First phase (mg/kg) Secondphase (mg/kg) I-6  2.5 4.0 I-14 5.2 3.1 I-23 1.5 1.0 I-29 3.6 3.5

Experimental Example 4 Inhibitory Effect on Compound 48/80-inducedPruritus in ICR Strain Mice

The experiment was carried out by the method of Inagaki et al. (Eur JPharmacol 1999;367:361-371) with some modifications. Briefly, the backof female ICR strain mice was clipped, and compound 48/80 (3 μg/50μL/site) was injected intradermally to elicit the response. The numberof scratching behavior to the injection site by hind paws, which wasobserved immediately after the injection, was counted for 30 min. Testcompounds, dissolved in sesame oil, were orally administered once. Afterthe injection of compound 48/80 at pre-determine time when the maximalplasma concentration of the compound was obtained. The inhibitory effectagainst pruritus was evaluated by comparing the number of scratching inthe compound-administered group with that in the vehicle-administeredgroup, and then ED50 value was calculated.

I-23 demonstrated a potent anti-pruritic effect with ED50 value of 0.54mg/kg.

Experimental Example 5 Bronchodilating Effect in Guinea Pigs

Under urethane anesthesia (1.4 g/kg, i.p.), acetylcholine (ACh) wasintravenously injected to guinea pigs by increasing doses of ACh every 5min, then bronchoconstrictor response observed immediately after eachACh injection was measured by the method of Konzett & Rössler with somemodifications. Briefly, trachea of guinea pigs was incised and a cannulawas attached to lung side. An artificial respirator (SN-480-7, Shinano)was connected to the cannula, and then a fixed amount of air (tidalvolume: 4 mL, ventilation frequency: 60 times/min) continuouslyinsufflated to maintain respiration. The insufflation pressureoverflowed from inhalation tube was monitored by a pressure transducer(TP-400T, Nihon Kohden) and recorded on a recorder (WT-645G, NihonKohden) through a carrier amplifier (AP-601G, Nihon Kohden). Testcompounds were administered orally 1 h before ACh injection, then theeffect on the dose-response curve of ACh was examined. Statisticalsignificance was analyzed concerning broncohdilating effect in guineapigs.

Formulation Example

The following formulation examples 1 to 8 are provided to furtherillustrate formulation example and are not to be construed as limitingthe scope of the present invention. The term “an active ingredient”means a compound of the present invention, a tautomer, a prodrug, apharmaceutical acceptable salt, or a solvate thereof. Formulationexample 1 Hard gelatin capsule are prepared using the followingingredients. Dosage (mg/capsule) Ingredients An actve ingredient 250Starch (dry) 200 Magnesium stearate 10 Total 460 mg Formulation 2Tablets are prepared using the following ingredients. Dosage (mg/tablet)Ingredients An actve ingredient 250 Cellulose (microcrystalline) 400Silicon dioxide (fume) 10 Stearic acid 5 Total 665 mg These ingredientsare mixed and condensed to prepare tablets of 665 mg. Formulation 3Aerosol solutions are prepared using the following ingredients. WeightIngredients An actve ingredient 0.25 Ethanol 25.75 Properanto 22(chlorodifluorometahne) 74.00 Total 100.00

An active ingredient and ethanol are mixed, and the mixture is addedinto a part of properanto 22, cooled at −30° C., transferred to packingequipment. The amount needed is provided to stainless steel vessel,diluted with residual properanto 22. The bubble unit is insalled tovessel. Formulation 4 Tablets containig an active ingredient 60 mg areprepared as folows. Ingredients An active ingredient 60 mg Starch 45 mgMicrocrystal cellulose 35 mg Polyvinylpyrrolidone (10% aqueous solution)4 mg Carboxymethyl starch sodium salt 4.5 mg Magnesium stearate 0.5 mgTalc 1 mg 150 mg

An active ingredient, Starch, and cellulose are made pass through a No.45 mesh U.S. sieve and then mixed sufficiently. The resulting mixture ismixed with a polyvinylpyrrolidone aqueous solution, made pass through aNo. 14 mesh U.S. sieve. The obtained granule is dried at 50° C., madepass through a No. 18 mesh U.S. sieve. To the granule are addedcarboxymethyl starch—Na, Magnesium stearate, and talc made pass througha No. 60 mesh U.S. sieve, and the mixture was mixed. The mixed powder iscompressed by tableting equipment to yield tablets of 150 mg.Formulation 5 Capsuls containig an active ingredient 80 mg are preparedas folows. Ingredients An active ingredient 80 mg Starch 59 mgMicrocrystal cellulose 59 mg Magnesium stearate  2 mg Total 200 mg

An active ingredient, Starch, cellulose, and magnesium stearate aremixed, made pass through a No. 45 mesh U.S. sieve, and then packed tohard gelatin capsuls at amount of 200 mg/capsul. Formulation 6Suppository containig an active ingredient 225 mg are prepared asfolows. Ingredients An active ingredient  225 mg Saturated fattyacidglyceride 2000 mg Total 2225 mg

An active ingredient is made pass through a No. 60 mesh U.S. sieve,suspended in saturated fattyacid glyceride dissolved by heating at aminimum of necessity. The mixture is cooled in the mould of 2mg.Formulation 7 Suspension containig an active ingredient 50 mg areprepared as folows. Ingredients An active ingredient 50 mgCarboxymethylcellulose sodium salt 50 mg Syrupus 1.25 mL Benzoic acidsolution 0.10 mL Aroma chemical q.v.   Pigmentum q.v._(—) Water Total 5mL

An active ingredient is made pass through a No. 60 mesh U.S. sieve,mixed with carboxymethylcellulose sodium salt and to prepare smoothlypaste. To the mixture are benzoic acid solution and syrupus which arediluted with a part of water, and the mixture is stirred. To the mixtureis residual water to prepare necessary volume. Formulation 8 Intravenousformulations are prepared as follows. Ingredients An active ingredient100 mg Saturated fattyacid glyceride 1000 ml

Usually a solution of ingredients above described is administeredintravenously to a patient by the speed of 1 ml/min.

Industrial Applicability

It was found that 2-naphthylimino-1,3-thiazine derivatives havingcannabinoid receptor agonistic acitivity exibit the effect as ananalgesics, a treating agent for algesic, an antipruritics or abronchodilator.

1. A compound represented by the formula (I):

wherein R² and R³ are the same or different and each is C2-C4 alkyl,C2-C4 alkenyl, C1-C4 alkoxyC1-C4 alkyl, optionally substitutedaminoC1-C4 alkyl, or C3-C6 cycloalkylC1-C4 alkyl; or R² and R³ are takentogether with the adjacent carbon atom to form an optionally substituted5 to 8 membered non-aromatic carbocyclic ring or an optionallysubstituted 5 to 8 membered non-aromatic heterocyclic ring; R⁴ is C1-C6alkyl, hydroxyC1-C6alkyl, optionally substituted aminoC1-C6alkyl, orC1-C6 alkoxyC1-C6 alkyl; X is an oxgen atom or a sulfur atom; A is thegroup of the formula:

wherein R¹ is, same or different, alkyl, alkoxy, alkylthio, optionallysubstituted amino, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted aralkyloxy, cycloalkyl, a halogen atom,hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl,carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxylalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyiminoalkyl,alkoxyalkoxy, alkylthioalkoxy, alkoxycarbonylalkoxy, carboxyalkoxy,alkylsulfonyloxy, optionally substituted heteroaryl, an optionallysubstituted non-aromatic heterocyclic group, cyano, cyanoalkoxy, or agroup of the formula: —C(═O)—R^(H) wherein R^(H) is a hydrogen atom,alkyl, optionally substituted aryl, or an optionally substitutednon-aromatic heterocyclic group; W is C2-C6 alkylene which may containan optionally substituted heteroatom(s) or C2-C4 alkenylene which maycontain an optionally substituted heteroatom(s); n is an integer of 0 to7; a pharmaceutically acceptable salt, or a solvate thereof.
 2. Thecompound according to claim 1 wherein R² and R³ are taken together withthe adjacent carbon atom to form an optionally substituted 5 to 6membered carbocyclic ring, a pharmaceutically acceptable salt, or asolvate thereof.
 3. The compound according to claim 1 or 2 wherein W is—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —N(CH₃)CH₂CH₂CH₂—, or—CH═CH—CH═CH—, a pharmaceutically acceptable salt, or a solvate thereof.4. A compound of the formula (II):

wherein R¹ is, same or different, alkyl, alkoxy, optionally substitutedamino, a halogen atom, hydroxy, haloalkyl, haloalkoxy, cyano, oralkoxycarbonylalkoxy; each of R² and R³ is, same or different, C2-C4alkyl; or R² and R³ are taken together with the adjacent carbon atom toform 5 to 6 membered cycloalkane; R⁴ is C1-C6 alkyl; X is an oxgen atomor a sulfur atom; n is an integer of O to 7; a pharmaceuticallyacceptable salt, or a solvate thereof.
 5. The compound according toclaim 4 wherein R¹ is a fluorine atom, a chlorine atom, dimethylamino,cyano, or t-butoxycarbonylmethoxy, a pharmaceutically acceptable salt,or a solvate thereof.
 6. The compound according to claim 4 or 5 whereinn is 0 or 1, a pharmaceutically acceptable salt, or a solvate thereof.7. A compound of the formula (II):

wherein R¹ is, same or different, alkyl, alkoxy, optionally substitutedamino, a halogen atom, hydroxy, haloalkyl, haloalkoxy, cyano, oralkoxycarbonylalkoxy; each of R² and R³ is, same or different, C2-C4alkyl; or R² and R³ are taken together with the adjacent carbon atom toform 5 to 6 membered cycloalkane; R⁴is C1-C6 alkyl; X is an oxgen atomor a sulfur atom; Z is —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, or —OCH₂CH₂O—; n isan integer of 0 to 3; a pharmaceutically acceptable salt, or a solvatethereof.
 8. The compound according to claim 7 wherein Z is —CH₂CH₂CH₂—or —CH₂CH₂CH₂CH₂—, a pharmaceutically acceptable salt, or a solvatethereof.
 9. The compound according to claim 7 wherein Z is —OCH₂CH₂O—, apharmaceutically acceptable salt, or a solvate thereof.
 10. The compoundaccording to claim 7 wherein n is 0, a pharmaceutically acceptable salt,or a solvate thereof.
 11. The compound according to any one of claim 4or 7 wherein R² and R³ are taken together with the adjacent carbon atomto form 6 membered cycloalkane, a pharmaceutically acceptable salt, or asolvate thereof.
 12. The compound according to any one of claims 1, 4and 7 wherein each of R² and R³ is, same or different, C2-C3 alkyl, apharmaceutically acceptable salt, or a solvate thereof.
 13. The compoundaccording to any one of claims 1, 4 and 7 wherein R⁴ is methyl or ethyl,a pharmaceutically acceptable salt, or a solvate thereof.
 14. Apharmaceutical composition which contains the compound according to anyone of claims 1, 4 and 7, a pharmaceutically acceptable salt, or asolvate thereof as an active ingredient.
 15. A pharmaceuticalcomposition which contains the compound according to any one of claims1, 4 and 7, which has a cannabinoid receptor agonistic activity, apharmaceutically acceptable salt, or a solvate thereof as an activeingredient,.
 16. The pharmaceutical composition according to claim 14which is useful for an analgesics.
 17. The pharmaceutical compositionaccording to claim 14 which is useful for a treating agent for algesic.18. The pharmaceutical composition according to claim 14 or which isuseful for an antipruritics.
 19. The pharmaceutical compositionaccording to claim 14 which is useful for a bronchodilator.
 20. A methodfor treating a disease related to a cannabinoid receptor which comprisesadministering the compound according to any one of claims 1, 4 and 7, apharmaceutically acceptable salt, or a solvate thereof.
 21. A method formanufacturing a treating agent for a disease related to a cannabinoidreceptor, a pharmaceutically acceptable salt, or a solvate thereof whichcomprises employing in said agent a compound according to any one ofclaims 1, 4 and
 7. 22. The pharmaceutical composition according to claim15 which is useful for an analgesics.
 23. The pharmaceutical compositionaccording to claim 15 which is useful for a treating agent for algesic.24. The pharmaceutical composition according claim 15 which is usefulfor an antipruritics.
 25. The pharmaceutical composition according toclaim 15 which is useful for a bronchodilator.